190 results on '"Nicholas J. Brandon"'
Search Results
102. Assessing the role of endooligopeptidase activity of Ndel1 (nuclear-distribution gene E homolog like-1) in neurite outgrowth
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Vitor Oliveira, Erik I. Charych, Mirian A. F. Hayashi, Juliano R. Guerreiro, Rosicler L. Barbosa, Akira Sawa, Nicholas J. Brandon, Antonio C.M. Camargo, Joana D'Arc Campeiro, Atsushi Kamiya, and Maurício F.M. Machado
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Neurons ,NDEL1 ,Neurite ,Mutant ,Metalloendopeptidases ,Cell Differentiation ,Nerve Tissue Proteins ,Endogeny ,Cell Biology ,Transfection ,Biology ,PC12 Cells ,Rats ,Cell biology ,Cellular and Molecular Neuroscience ,DISC1 ,RNA interference ,Mutation ,Neurites ,biology.protein ,Animals ,Heterologous expression ,RNA, Small Interfering ,Carrier Proteins ,Molecular Biology - Abstract
Ndel1 plays multiple roles in neuronal development but it is unknown whether its reported cysteine protease activity is important for these processes. Ndel1 is known to be critical for neurite outgrowth in PC12 cells where it works co-operatively in a complex with DISC1 to allow normal neuritogenesis. Through an initial interest in understanding the regulation of the expression of Ndel1 during neuronal differentiation, we have been able to show that Ndel1 expression and enzyme activity is up-regulated during neurite outgrowth in PC12 cells induced to neural differentiation. Heterologous expression of wild-type Ndel1 (Ndel1WT) in PC12 cells increases the percentage of cells bearing neurites in contrast to the catalytically dead mutant, Ndel1C273A, which caused a decrease. Furthermore depletion of endogenous Ndel1 by RNAi decreased neurite outgrowth, which was rescued by transfection of the enzymatically active Ndel1WT, but not by the Ndel1C273A mutant. Together these data support the notion that the endooligopeptidase activity of Ndel1 plays a crucial role in the differentiation process of PC12 cells to neurons. Genetic data and protein interaction with DISC1 might suggest a role for Ndel1 in neuropsychiatirc conditions.
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- 2010
103. Interplay of Palmitoylation and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for the Treatment of Schizophrenia
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Nicholas J. Brandon, Li-Xin Jiang, Kelly Sullivan, Frederick Lo, and Erik I. Charych
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Threonine ,Lipoylation ,Palmitates ,Biology ,Transfection ,Medium spiny neuron ,Mice ,Cytosol ,Palmitoylation ,Animals ,Humans ,Hypoglycemic Agents ,Immunoprecipitation ,Cysteine ,Phosphorylation ,Protein kinase A ,Cyclic GMP ,Cells, Cultured ,Neurons ,Analysis of Variance ,Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,Microscopy, Confocal ,Cyclic nucleotide phosphodiesterase ,Phosphoric Diester Hydrolases ,General Neuroscience ,Phosphodiesterase ,Articles ,Embryo, Mammalian ,Subcellular localization ,Corpus Striatum ,Rats ,Cell biology ,Protein Transport ,Mutagenesis, Site-Directed ,PDE10A ,Oligopeptides - Abstract
Phosphodiesterase 10A (PDE10A) is a striatum-enriched, dual-specific cyclic nucleotide phosphodiesterase that has gained considerable attention as a potential therapeutic target for psychiatric disorders such as schizophrenia. As such, a PDE10A-selective inhibitor compound, MP-10, has recently entered clinical testing. Since little is known about the cellular regulation of PDE10A, we sought to elucidate the mechanisms that govern its subcellular localization in striatal medium spiny neurons. Previous reports suggest that PDE10A is primarily membrane bound and is transported throughout medium spiny neuron axons and dendrites. Moreover, it has been shown in PC12 cells that the localization of the major splice form, PDE10A2, may be regulated by protein kinase A phosphorylation at threonine 16 (Thr-16). Using an antibody that specifically recognizes phosphorylated Thr-16 (pThr-16) of PDE10A2, we provide evidence that phosphorylation at Thr-16 is critical for the regulation of PDE10A subcellular localization in vivo. Furthermore, we demonstrate in primary mouse striatal neuron cultures that PDE10A membrane association and transport throughout dendritic processes requires palmitoylation of cysteine 11 (Cys-11) of PDE10A2, likely by the palmitoyl acyltransferases DHHC-7 and -19. Finally, we show that Thr-16 phosphorylation regulates PDE10A trafficking and localization by preventing palmitoylation of Cys-11 rather than by interfering with palmitate–lipid interactions. These data support a model whereby PDE10A trafficking and localization can be regulated in response to local fluctuations in cAMP levels. Given this, we propose that excessive striatal dopamine release, as occurs in schizophrenia, might exert differential effects on the regulation of PDE10A localization in the two striatal output pathways.
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- 2010
104. Discovery of Imidazo[1,5-a]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitiors
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Thorsten Hage, Nicholas J. Brandon, Norbert Höfgen, Hans-Joachim Lankau, Menelas N. Pangalos, Christian Grunwald, Karen L. Marquis, Michael S. Malamas, Rudolf Schindler, Thomas Kronbach, Hans Stange, Peter Tremmel, Barbara Langen, Ute Egerland, and Boyd L. Harrison
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Models, Molecular ,Quantitative structure–activity relationship ,Phosphodiesterase Inhibitors ,Phosphoric Diester Hydrolases ,Protein Conformation ,Stereochemistry ,Chemistry ,Quantitative Structure-Activity Relationship ,Phosphodiesterase ,In vitro ,Rats ,Stereotypy (non-human) ,Pyrazines ,Drug Discovery ,Hydrolase ,Animals ,Humans ,Molecular Medicine ,Female ,PDE10A ,Rats, Wistar ,Binding site - Abstract
Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
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- 2010
105. O10.7. INVESTIGATING THE MECHANISMS UNDERLYING THE BENEFICIAL EFFECTS OF ESTROGENS IN SCHIZOPHRENIA
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Sagnik Bhattacharyya, Carol Shum, Deepak Srivastava, Jack Price, P J Michael Deans, Rodrigo R.R. Duarte, Marco Conforti, Nicholas J. Brandon, and Leo W. Perfect
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Psychiatry and Mental health ,Abstracts ,business.industry ,Schizophrenia (object-oriented programming) ,Medicine ,business ,Neuroscience ,Beneficial effects ,O10. Oral Session: Risk Factors - Abstract
Background Estrogens, in particular 17β-estradiol (estradiol) have repeatedly been shown to exert powerful influences over cognitive function, and in particular, on a range of cognitive behaviours associated with neurodevelopmental disorders. This includes depressive and anxious behaviours as well as learning and memory (including working memory). These cognitive enhancing effects have been shown to be dependent on increases in the number of dendritic spines as well as alterations in glutamate receptor transmission and regulation of synaptic protein expression. Modulation of these synaptic functions can result in long-term increases in synaptic connectivity. Interestingly, there is growing evidence that estrogenic-based compounds may have a positive effect in the treatment of a number of neuropsychiatric disorders, including schizophrenia. Importantly, recent clinical studies have demonstrated that adjunct treatment with estradiol or the selective estrogen receptor modulator (SERM) raloxifene, ameliorates positive and negative symptoms and improves working memory and attention deficits in male and female schizophrenic patients. However, it has been argued that estrogenic-based compounds are not an effective treatment option owing to potential serve side effects associated with long-term administration. It is, however, of note that the precise mechanisms that underlie the positive effects of estradiol, or estrogenic-based compounds, in this disease are currently unclear. Therefore, determining how estradiol exerts its positive effects in health as well as in disease, will aid in the development of safer and more effective estrogenic-based compounds. Methods Here, we have used human induced pluripotent stem cell (iPSC)-derived from healthy or patients diagnosed schizophrenic but with no common genetic background to study the potential mechanism that may underlie estrogens beneficial effects in disease. iPSCs were differentiated into young, developing, cortical neurons using well established methods. First, we assessed the ability of estrogens to modulate key neuronal and synaptic structures as well as synaptic and inflammatory genes. Next, we assessed the expression and distribution of synaptic proteins were determined in both healthy iPSC-neurons and patient iPSC-neurons (from 3–6 individuals from each group). Subsequently, using a pharmacological approach, we have explored the ability of estrogens to rescue cellular and molecular deficits in iPSC-neurons derived from schizophrenic patients. Results Both healthy and patient iPSC differentiated into neuroepithelium, neural progenitors cells and finally into TBR1- and EMX1-positive neurons efficiently. Assessment of synaptic protein expression revealed reduced expression of key synaptic proteins involved in excitatory transmission compared to control lines. When healthy iPSC-neurons were treated with a range of estrogenic compounds, we observed a robust increase in the expression of key synaptic protein including GRIN1 and DGL4. Consistent with previous reports, patient iPSC-neurons displayed reduced synaptic protein expression compared with healthy iPSC-neurons. Critically, when patient iPSC-neurons were treated with 17β-estradiol or raloxifene, we observed an increase in synaptic protein expression to a level similar to that observed in untreated healthy iPSC-neurons. Discussion These data are the first to demonstrate that estrogens are capable of regulating synaptic proteins in human neurons taken from patients diagnosed with schizophrenia. Collectively, we hope these data will help us understand how estrogens may confer their positive effects in psychiatric disorders.
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- 2018
106. Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes
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Richard J. Murrills, Miles D. Houslay, Sheree F. Logue, May Tam, Cody Kelley, Thomas A. Comery, Steven M. Grauer, Jason M. Dwyer, Julie A. Brennan, Rachel Navarra, Michael J. Agostino, Virginia L. Pulito, Jonathon P. Day, Li-Xin Jiang, Sarah J. Neal, Nicholas J. Brandon, Brian J. Platt, Stacey J. Sukoff Rizzo, Subha Lakkaraju, Xiaotian Zhong, and Michy P. Kelly
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Male ,medicine.medical_specialty ,Glutamine ,Hippocampus ,AMPA receptor ,Biology ,Receptors, N-Methyl-D-Aspartate ,Gene Expression Regulation, Enzymologic ,Mice ,3',5'-Cyclic-GMP Phosphodiesterases ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Social Behavior ,Receptor ,Mice, Knockout ,Multidisciplinary ,Arc (protein) ,Behavior, Animal ,Mental Disorders ,Glutamate receptor ,Subiculum ,Phosphodiesterase ,Biological Sciences ,Mice, Inbred C57BL ,Phenotype ,Endocrinology ,Female ,Signal transduction ,Signal Transduction - Abstract
Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A −/− knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatric-disease–related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N -methyl- D -aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate α-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor–associated proteins stargazin (γ2) and γ8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.
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- 2010
107. Disrupted-in-Schizophrenia-1 (DISC1) regulates spines of the glutamate synapse via Rac1
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Hannah Murdoch, Zhong Xie, Miles D. Houslay, Zhen Yan, Manabu Takaki, Akira Sawa, Deepak Srivastava, Yuichi Makino, Nicholas J. Brandon, Toshifumi Tomoda, Nicholas M. Graziane, Akiko Hayashi-Takagi, Allan J. Dunlop, Jay M. Baraban, Anupamaa J Seshadri, Koko Ishizuka, Peter Penzes, Saurav Seshadri, and Atsushi Kamiya
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rac1 GTP-Binding Protein ,Dendritic spine ,Time Factors ,Dendritic Spines ,Glutamic Acid ,RAC1 ,Nerve Tissue Proteins ,Neurotransmission ,Receptors, N-Methyl-D-Aspartate ,Article ,Rats, Sprague-Dawley ,Tissue Culture Techniques ,03 medical and health sciences ,DISC1 ,Glutamatergic ,0302 clinical medicine ,Animals ,Guanine Nucleotide Exchange Factors ,Receptors, AMPA ,Cells, Cultured ,030304 developmental biology ,Cerebral Cortex ,Neurons ,0303 health sciences ,biology ,General Neuroscience ,Glutamate receptor ,Excitatory Postsynaptic Potentials ,Rats ,Gene Knockdown Techniques ,Synapses ,biology.protein ,NMDA receptor ,RNA Interference ,Signal transduction ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. Here we describe a role for the schizophrenia risk factor, Disrupted-in-Schizophrenia 1 (DISC1), in the maintenance of spine morphology and function. We show that DISC1 anchors Kalirin-7 (Kal-7) thereby regulating access of Kal-7 to Rac1 and so controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in cortical culture as well as in vivo brain. This offers explanation for why Rac1 and its activator (Kal-7) serve as key mediators of spine enlargement and that constitutive Rac1 activation decreases spine size. This novel mechanism likely underlies disturbances in glutamatergic neurotransmission frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a “signalosome” involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.
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- 2010
108. Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus
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Cédrick Florian, Guido Michels, Stephen J. Moss, Rachel Jurd, Catriona M. Houston, Robbert Havekes, Ted Abel, Verena Tretter, Mansi Vithlani, Miho Terunuma, Raquel Revilla-Sanchez, Andrés Couve, Trevor G. Smart, Werner Sieghart, and Nicholas J. Brandon
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Male ,medicine.medical_specialty ,Patch-Clamp Techniques ,Spatial Behavior ,Hippocampus ,Biology ,Inhibitory postsynaptic potential ,gamma-Aminobutyric acid ,Mice ,chemistry.chemical_compound ,Memory ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,Gene Knock-In Techniques ,Phosphorylation ,Tyrosine ,Multidisciplinary ,GABAA receptor ,Tyrosine phosphorylation ,Biological Sciences ,Receptors, GABA-A ,Mice, Inbred C57BL ,Endocrinology ,nervous system ,chemistry ,Mutation ,Neuroscience ,medicine.drug - Abstract
Fast synaptic inhibition in the brain is largely mediated by γ-aminobutyric acid receptors (GABA A R). While the pharmacological manipulation of GABA A R function by therapeutic agents, such as benzodiazepines can have profound effects on neuronal excitation and behavior, the endogenous mechanisms neurons use to regulate the efficacy of synaptic inhibition and their impact on behavior remains poorly understood. To address this issue, we created a knock-in mouse in which tyrosine phosphorylation of the GABA A Rs γ2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated. These animals exhibited enhanced GABA A R accumulation at postsynaptic inhibitory synaptic specializations on pyramidal neurons within the CA3 subdomain of the hippocampus, primarily due to aberrant trafficking within the endocytic pathway. This enhanced inhibition correlated with a specific deficit in spatial object recognition, a behavioral paradigm dependent upon CA3. Thus, phospho-dependent regulation of GABA A R function involving just two tyrosine residues in the γ2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.
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- 2009
109. Estrogen Receptor Neurobiology and its Potential for Translation into Broad Spectrum Therapeutics for CNS Disorders
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Feng Liu, Karen L. Marquis, Luis C Muñiz, Garth T. Whiteside, Robert H. Ring, Nicholas J. Brandon, Menelas N. Pangalos, and Zoë A. Hughes
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Central Nervous System ,medicine.drug_class ,Neurogenesis ,Synaptogenesis ,Pain ,Estrogen receptor ,Anxiety ,Biology ,Neurobiology ,Alzheimer Disease ,medicine ,Animals ,Estrogen Receptor beta ,Humans ,Pain Management ,Transcription factor ,Neuroinflammation ,Inflammation ,Regulation of gene expression ,Depressive Disorder ,Neurosecretion ,Estrogen Receptor alpha ,Estrogens ,General Medicine ,Gene Expression Regulation ,Estrogen ,Synaptic plasticity ,Schizophrenia ,Signal transduction ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,Transcription Factors - Abstract
Estrogens are hormones that modulate a diverse array of effects during development and adulthood. The effects of estrogen are mediated by two estrogen receptor (ER) isotypes, ERalpha and ERbeta, which classically function as transcription factors to modulate specific target gene expression and in addition regulate a growing list of intracellular signaling cascades. These receptors share protein sequence homology and protein-motif organization but have distinct differences in their tissue distribution and binding affinities for their ligands. In the nervous system estrogen has been implicated to play a role in a number of processes which regulate synaptic plasticity including synaptogenesis and neurogenesis. The role for estrogen in a range of neurological and neuropsychiatric diseases is also becoming very apparent. Estrogen is able to regulate processes and behaviours relevant for both Alzheimer's disease and schizophrenia and to modulate neuroendocrine and inflammatory processes important in neuroinflammation, anxiety and depressive disorders as well as chronic pain. We will consider the rationale for estrogen-based therapies for diseases of the nervous system. In particular we will highlight the molecular mechanisms and signal transduction pathways most likely underlying the effects of estrogen in the CNS.
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- 2009
110. Cytoskeletal Changes Underlie Estrogen's Acute Effects on Synaptic Transmission and Plasticity
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Lulu Y. Chen, Enikö A. Kramár, Christopher S. Rex, Gary Lynch, Feng Liu, Nicholas J. Brandon, and Christine M. Gall
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Male ,Patch-Clamp Techniques ,RHOA ,Dendritic spine ,Ginsenosides ,Long-Term Potentiation ,Hippocampus ,Synaptic Transmission ,GABA Antagonists ,Rats, Sprague-Dawley ,Neural Pathways ,Picrotoxin ,Fulvestrant ,Oxazoles ,Cytoskeleton ,Neurons ,Microscopy, Confocal ,Neuronal Plasticity ,Estradiol ,biology ,General Neuroscience ,Age Factors ,Estrogen Antagonists ,Long-term potentiation ,Cofilin ,Cell biology ,Thiazolidines ,Female ,Signal Transduction ,medicine.medical_specialty ,Sapogenins ,medicine.drug_class ,Dendritic Spines ,Ovariectomy ,Biophysics ,macromolecular substances ,In Vitro Techniques ,Filamentous actin ,Article ,Lim kinase ,Phenols ,Internal medicine ,medicine ,Animals ,Rats, Long-Evans ,Analysis of Variance ,Dose-Response Relationship, Drug ,Excitatory Postsynaptic Potentials ,Estrogens ,Bridged Bicyclo Compounds, Heterocyclic ,Actins ,Electric Stimulation ,Rats ,Endocrinology ,Animals, Newborn ,Estrogen ,biology.protein ,Latrunculin ,Excitatory Amino Acid Antagonists - Abstract
Estrogen, in addition to its genomic effects in brain, causes rapid and reversible changes to synaptic operations. We report here that these acute actions are due to selective activation of an actin-signaling cascade normally used in the production of long-term potentiation (LTP). Estrogen, or a selective agonist of the steroid's β-receptor, caused a modest increase in fast glutamatergic transmission and a pronounced facilitation of LTP in adult hippocampal slices; both effects were completely eliminated by latrunculin, a toxin that prevents actin filament assembly. Estrogen also increased spine concentrations of filamentous actin and strongly enhanced its polymerization in association with LTP. A search for the origins of these effects showed that estrogen activates the small GTPase RhoA and phosphorylates (inactivates) the actin severing protein cofilin, a downstream target of RhoA. Moreover, an antagonist of RhoA kinase (ROCK) blocked estrogen's synaptic effects. Estrogen thus emerges as a positive modulator of a RhoA>ROCK>LIM kinase>cofilin pathway that regulates the subsynaptic cytoskeleton. It does not, however, strongly affect a second LTP-related pathway, involving the GTPases Rac and Cdc42 and their effector p21-activated kinase, which may explain why its acute effects are reversible. Finally, ovariectomy depressed RhoA activity, spine cytoskeletal plasticity, and LTP, whereas brief infusions of estrogen rescued plasticity, suggesting that the deficits in plasticity arise from acute, as well as genomic, consequences of hormone loss.
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- 2009
111. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1–ErbB4 and DISC1
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Akira Sawa, Saurav Seshadri, Atsushi Kamiya, Hanna Jaaro-Peled, Akiko Hayashi-Takagi, and Nicholas J. Brandon
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Psychosis ,Receptor, ErbB-4 ,Neuregulin-1 ,Nerve Tissue Proteins ,Disease ,Article ,DISC1 ,Genetic predisposition ,medicine ,Animals ,Humans ,Mechanisms of schizophrenia ,Neuregulin 1 ,biology ,Mechanism (biology) ,General Neuroscience ,Brain ,Gene Expression Regulation, Developmental ,medicine.disease ,ErbB Receptors ,Disease Models, Animal ,Schizophrenia ,biology.protein ,Psychology ,Neuroscience - Abstract
Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.
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- 2009
112. Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of the Positive, Cognitive, and Negative Symptoms of Schizophrenia
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Li-Xin Jiang, Steven M. Grauer, Feng Liu, Sheree F. Logue, Nicholas J. Brandon, Barbara Langen, Michael S. Malamas, Ute Egerland, Rachel Navarra, Cody Kelley, Erik I. Charych, Thomas A. Comery, Michy P. Kelly, Karen L. Marquis, Radka Graf, Thorsten Hage, Julie A. Brennan, and Virginia L. Pulito
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Male ,Reflex, Startle ,Apomorphine ,Phosphodiesterase Inhibitors ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Glutamatergic ,Cognition ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Social Behavior ,Receptor ,Prepulse inhibition ,Catalepsy ,Mice, Inbred BALB C ,Sensory gating ,Phosphoric Diester Hydrolases ,Reverse Transcriptase Polymerase Chain Reaction ,Dopaminergic ,Phosphodiesterase ,Rats ,Mice, Inbred C57BL ,Neostriatum ,medicine.anatomical_structure ,Quinolines ,Pyrazoles ,Molecular Medicine ,Schizophrenic Psychology ,PDE10A ,Dizocilpine Maleate ,Stereotyped Behavior ,Psychology ,Excitatory Amino Acid Antagonists ,Antipsychotic Agents ,medicine.drug - Abstract
Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.
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- 2009
113. Ndel1 alters its conformation by sequestering cAMP-specific phosphodiesterase-4D3 (PDE4D3) in a manner that is dynamically regulated through Protein Kinase A (PKA)
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Daniel M. Collins, Miles D. Houslay, Anke Prinz, Hannah Murdoch, Friedrich W. Herberg, Nicholas J. Brandon, Qi Wang, Erik I. Charych, Allan J. Dunlop, and George S. Baillie
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Gene isoform ,Protein Conformation ,Biology ,DISC1 ,1-Methyl-3-isobutylxanthine ,Chlorocebus aethiops ,Cyclic AMP ,Animals ,Humans ,Immunoprecipitation ,Protein Isoforms ,Phosphorylation ,Protein kinase A ,Cells, Cultured ,Binding Sites ,NDEL1 ,Colforsin ,Phosphodiesterase ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Cell biology ,Energy Transfer ,Biochemistry ,COS Cells ,Second messenger system ,biology.protein ,Phosphodiesterase 4 Inhibitors ,Carrier Proteins ,CREB1 - Abstract
The involvement of the Nuclear distribution element-like (Ndel1; Nudel) protein in the recruitment of the dynein complex is critical for neurodevelopment and potentially important for neuronal disease states. The PDE4 family of phosphodiesterases specifically degrades cAMP, an important second messenger implicated in learning and memory functions. Here we show for the first time that Ndel1 can interact directly with PDE4 family members and that the interaction of Ndel1 with the PDE4D3 isoform is uniquely disrupted by elevation of intracellular cAMP levels. While all long PDE4 isoforms are subject to stimulatory PKA phosphorylation within their conserved regulatory UCR1 domain, specificity for release of PDE4D3 is conferred due to the PKA-dependent phosphorylation of Ser13 within the isoform-specific, unique amino-terminal domain of PDE4D3. Scanning peptide array analyses identify a common region on Ndel1 for PDE4 binding and an additional region that is unique to PDE4D3. The common site lies within the stutter region that links the second coiled-coil region to the unstable third coiled-coil regions of Ndel1. The additional binding region unique to PDE4D3 penetrates into the start of the third coiled-coil region that can undergo tail-to-tail interactions between Ndel1 dimers to form a 4 helix bundle. We demonstrate Ndel1 self-interaction in living cells using a BRET approach with luciferase- and GFP-tagged forms of Ndel1. BRET assessed Ndel1–Ndel1 self-interaction is amplified through the binding of PDE4 isoforms. For PDE4D3 this effect is ablated upon elevation of intracellular cAMP due to PKA-mediated phosphorylation at Ser13, while the potentiating effects of PDE4B1 and PDE4D5 are resistant to cAMP elevation. PDE4D long isoforms and Ndel1 show a similar sub-cellular distribution in hippocampus and cortex and locate to post-synaptic densities. We show that Ndel1 sequesters EPAC, but not PKA, in order to form a cAMP signalling complex. We propose that a key function of the Ndel1 signalling scaffold is to signal through cAMP by sequestering EPAC, whose activity may thus be specifically regulated by sequestered PDE4 that also stabilizes Ndel1–Ndel1 self-interaction. In the case of PDE4D3, its association with Ndel1 is dynamically regulated by PKA input through its ability to phosphorylate Ser13 in the unique N-terminal region of this isoform, triggering the specific release of PDE4D3 from Ndel1 when cAMP levels are elevated. We propose that Ser13 may act as a redistribution trigger in PDE4D3, allowing it to dynamically re-shape cAMP gradients in distinct intracellular locales upon its phosphorylation by PKA.
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- 2008
114. ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities
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Steven M. Grauer, Peter J. Atkinson, Michael A. Olsen, Cody Kelley, Deborah L. Smith, Margaret Lai, Guoming Zhang, Feng Liu, Sharon Rosenzweig-Lipson, Chad E. Beyer, Michael Popiolek, Adam M. Gilbert, Mark Day, Karen L. Marquis, Radka Graf, Rachel Navarra, Claudine Pulicicchio, Farhana Pruthi, Xavier Z. Khawaja, Evguenia Kouranova, Sheree F. Logue, Tom A. Comery, Caitlin Wantuch, Mark H. Pausch, and Nicholas J. Brandon
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Allosteric modulator ,Receptor, Metabotropic Glutamate 5 ,Allosteric regulation ,Drug Evaluation, Preclinical ,Prefrontal Cortex ,CDPPB ,Pharmacology ,Receptors, Metabotropic Glutamate ,Hippocampus ,Cell Line ,Cognition ,Allosteric Regulation ,Piperidines ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Humans ,Phencyclidine ,Brain Chemistry ,Oxadiazoles ,Dose-Response Relationship, Drug ,Metabotropic glutamate receptor 5 ,Chemistry ,Glutamate receptor ,Rats ,Metabotropic glutamate receptor ,Molecular Medicine ,Antipsychotic Agents ,medicine.drug - Abstract
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.
- Published
- 2008
115. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory
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Cody Kelley, Stephen J. Moss, Daniel Bitran, Ronald F. Mervis, Rachel Navarra, Raquel Revilla-Sanchez, Amy Sung, Mark Day, Guoming Zhang, Nicholas J. Brandon, Feng Liu, Luis C Muñiz, Karen L. Marquis, Warren D. Hirst, Robert L. Arias, Menelas N. Pangalos, Steven M. Grauer, Peter H. Reinhart, and Virginia L. Pulito
- Subjects
Male ,Agonist ,medicine.drug_class ,Dendritic Spines ,Ovariectomy ,Long-Term Potentiation ,Estrogen receptor ,Biology ,Hippocampal formation ,Hippocampus ,Synaptic Transmission ,Mice ,Organ Culture Techniques ,Memory ,medicine ,Animals ,Estrogen Receptor beta ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Maze Learning ,skin and connective tissue diseases ,Estrogen receptor beta ,Mice, Knockout ,Neurons ,Neuronal Plasticity ,Estradiol ,General Neuroscience ,Estrogens ,Long-term potentiation ,Rats ,Mice, Inbred C57BL ,body regions ,medicine.anatomical_structure ,nervous system ,Knockout mouse ,Synaptophysin ,biology.protein ,Female ,Neuron ,Neuroscience - Abstract
Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
- Published
- 2008
116. How has DISC1 enabled drug discovery?
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Hanna Jaaro-Peled, Akira Sawa, Nicholas J. Brandon, and Qi Wang
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Neurocognitive Disorders ,Nerve Tissue Proteins ,Computational biology ,Disease ,Biology ,Bioinformatics ,Synaptic Transmission ,Interactome ,Cellular and Molecular Neuroscience ,DISC1 ,Interaction network ,RNA interference ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Drug discovery ,Brain ,Cell Biology ,medicine.disease ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Disease Models, Animal ,Schizophrenia ,Drug Design ,biology.protein ,Identification (biology) ,Carrier Proteins - Abstract
Growing genetic and clinical evidence has shown that disrupted-in-schizophrenia 1 (DISC1) is one of the most compelling risk genes for schizophrenia and other major mental disorders. The understanding of the role that DISC1 plays in neuronal development and cell signaling has been greatly enhanced by the identification of DISC1 binding partners, an appreciation of its expression during development and functional studies using RNA interference. But what is the impact of this explosion of data for psychiatric drug discovery? Though we are at a very early stage of our understanding of DISC1 biology, it is an important time to review what has already been achieved and to discuss its impact. DISC1 biology has enabled the identification of new therapeutic targets in the form of DISC1 binding partners and other molecules found within a large DISC1 interaction network, the so-called 'DISC1 interactome'. We will review the better characterized of these interactions and also emphasize the richness of potential targets in the more poorly studied areas of the interactome. Furthermore, DISC1 has encouraged the development of new animal models for psychiatric disorders, which is critical for the study of disease biology. Thus, DISC1 may have the potential to not only point us in the direction of novel drug targets but also provide more relevant animal models for compound testing.
- Published
- 2008
117. Dissecting DISC1 function through protein–protein interactions
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Nicholas J. Brandon
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Genetics ,NDEL1 ,biology ,Schizophrenia (object-oriented programming) ,Nerve Tissue Proteins ,Computational biology ,Biochemistry ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Protein–protein interaction ,Mice ,DISC1 ,PDE4B ,biology.protein ,Animals ,Humans ,Identification (biology) ,Carrier Proteins ,Gene ,Function (biology) ,Protein Binding - Abstract
Disrupted in schizophrenia 1 (DISC1) is emerging in the eyes of many as the most promising candidate of all the schizophrenia risk genes. This viewpoint is derived from the combination of genetic, clinical, imaging and rapidly advancing cell biology data around this gene. All of these areas have been reviewed extensively recently and this review will point you towards some of these excellent papers. My own personal view of the potential importance of DISC1 was echoed in a recent review which suggested that DISC1 may be a ‘Rosetta Stone’ for schizophrenia research [Ross, Margolis, Reading, Pletnikov and Coyle (2006) Neuron 52, 139–153]. Our own efforts to try to understand the function of DISC1 were through identification of its protein-binding partners. Through an extensive Y2H (yeast two-hybrid) and bioinformatics effort we generated the ‘DISC1-Interactome’, a comprehensive network of protein–protein interactions around DISC1. In two excellent industry–academia collaborations we focused on two main interacting partners: Ndel1 (nudE nuclear distribution gene E homologue-like 1), an enigmatic protein which may have diverse functions as both a cysteine protease and a key centrosomal structural protein; and PDE4B, a cAMP-specific phosphodiesterase. I will review the work around these two protein complexes in detail.
- Published
- 2007
118. State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects
- Author
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Colleen M. Niswender, Michael R. Wood, Thomas M. Bridges, Michael Bubser, Mark E. Duggan, P. Jeffrey Conn, Magnus Ivarsson, Carrie K. Jones, Nicholas J. Brandon, Michael W. Wood, Xuewen Gong, Robert W. Gould, John Dunlop, J. Scott Daniels, Michael T. Nedelcovych, Meredith J. Noetzel, Erica Tsai, and Craig W. Lindsley
- Subjects
0301 basic medicine ,Male ,medicine.drug_class ,Polysomnography ,Thiophenes ,Non-rapid eye movement sleep ,Article ,Arousal ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Allosteric Regulation ,medicine ,Animals ,Neuroscience of sleep ,Clozapine ,Pharmacology ,medicine.diagnostic_test ,Receptor, Muscarinic M4 ,musculoskeletal, neural, and ocular physiology ,Electroencephalography ,Rats ,Pyridazines ,030104 developmental biology ,chemistry ,Anesthesia ,Sedative ,Sleep onset ,Xanomeline ,Psychology ,Sleep ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal by delaying Rapid Eye Movement (REM) sleep onset, selectively increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.
- Published
- 2015
119. Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity
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Barbara Duff, Andrew M. McIntosh, Nicholas J. Brandon, Neil Roberts, Stephen Giles, Emma Sprooten, Bill Moorhead, Zoë A. Hughes, Jeremy Hall, Pippa A. Thomson, Liana Romaniuk, Scott Semple, Rali Dimitrova, Maria R. Dauvermann, Andrew Watson, Heather C. Whalley, Stephen M. Lawrie, Mark E. Bastin, Brandon Whitcher, John Dunlop, and Douglas Blackwood
- Subjects
Male ,Bipolar Disorder ,Genu of the corpus callosum ,Schizophrenia/genetics ,White Matter/pathology ,lcsh:Medicine ,translocation ,Chromosomal translocation ,Corpus callosum ,Chromosomes, Human, Pair 11/genetics ,Severity of Illness Index ,Translocation, Genetic ,Corpus Callosum ,corpus callosum ,Exons/genetics ,Nerve Tissue Proteins/deficiency ,lcsh:Science ,Genetics ,Multidisciplinary ,biology ,Bipolar Disorder/genetics ,White matter ,Exons ,Middle Aged ,Cyclothymic Disorder/genetics ,White Matter ,Cyclothymic Disorder ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Chromosomes, Human, Pair 1/genetics ,Chromosomes, Human, Pair 1 ,Female ,Depressive Disorder, Major/genetics ,Research Article ,Adult ,medicine.medical_specialty ,Psychosis ,Adolescent ,Nerve Tissue Proteins ,Young Adult ,DISC1 ,Fractional anisotropy ,medicine ,Humans ,Bipolar disorder ,Psychiatry ,Depressive Disorder, Major ,Chromosomes, Human, Pair 11 ,lcsh:R ,medicine.disease ,R1 ,schizophrenia ,Schizophrenia ,biology.protein ,lcsh:Q ,Corpus Callosum/pathology - Abstract
Objective\ud \ud Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3).\ud Method\ud \ud Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33).\ud Results\ud \ud We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity.\ud Conclusions\ud \ud We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.
- Published
- 2015
120. Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo
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Tarek Z. Deeb, Mark E. Duggan, Jamie Maguire, Nicholas J. Brandon, Stephen J. Moss, Liliya Silayeva, Matt R. Kelley, John Dunlop, Sudhir Sivakumaran, Stephen Zicha, Robert J. Mather, Ross A. Cardarelli, Yvonne E. Moore, Jayanta Mukherjee, and Danielle H. Morrow
- Subjects
Hippocampus ,Neurotransmission ,Hippocampal formation ,Biology ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Membrane Potentials ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Organ Culture Techniques ,Sodium Potassium Chloride Symporter Inhibitors ,Premovement neuronal activity ,Animals ,Humans ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Symporters ,GABAA receptor ,General Neuroscience ,Depolarization ,3. Good health ,Rats ,Mice, Inbred C57BL ,HEK293 Cells ,nervous system ,Animals, Newborn ,GABAergic ,Brief Communications ,Neuroscience ,030217 neurology & neurosurgery - Abstract
GABAAreceptors form Cl−permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K+/Cl−cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl−levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices andin vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift inEGABAvalues and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg2+conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factorex vivoandin vivo.
- Published
- 2015
121. Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1
- Author
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Sanbing Shen, Neil Dawson, Brian J. Morris, J. R. Hedde, Nicholas J. Brandon, J Brown, David M. Thomson, John Dunlop, Allan McVie, Judith A. Pratt, Mai Kurihara, Zoë A. Hughes, Patricia A. Seymour, Andrew D. Randall, and Catherine L Winchester
- Subjects
endocrine system ,RM ,Patch-Clamp Techniques ,Glutamic Acid ,Prefrontal Cortex ,Hippocampus ,Mice, Transgenic ,Nerve Tissue Proteins ,mental-illness ,Hippocampal formation ,Neurotransmission ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,129s6/svev strain ,drug discovery ,Mice ,Cellular and Molecular Neuroscience ,Glutamatergic ,DISC1 ,Thalamus ,Neural Pathways ,Animals ,in-schizophrenia 1 ,Prefrontal cortex ,CA1 Region, Hippocampal ,behavioral phenotypes ,Biological Psychiatry ,synaptic plasticity ,prepulse inhibition ,biology ,parvalbumin-immunoreactive neurons ,Glutamate receptor ,Brain ,affective-disorders ,Mice, Inbred C57BL ,Psychiatry and Mental health ,nervous system ,biology.protein ,RC0321 ,Autoradiography ,NMDA receptor ,Ketamine ,Original Article ,Excitatory Amino Acid Antagonists ,Neuroscience ,medial prefrontal cortex - Abstract
Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity.
- Published
- 2015
122. KCC2 activity is critical in limiting the onset and severity of status epilepticus
- Author
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Liliya Silayeva, Jaime L. Maguire, Rochelle M. Hines, Tarek Z. Deeb, Matt R. Kelley, John Dunlop, Nicholas J. Brandon, Henry H.C. Lee, Paul Davies, Stephen J. Moss, and Michaelanne B. Munoz
- Subjects
medicine.medical_specialty ,Kainate receptor ,Status epilepticus ,Biology ,Epileptogenesis ,gamma-Aminobutyric acid ,Dephosphorylation ,Mice ,Mice, Neurologic Mutants ,Phosphoserine ,Status Epilepticus ,Chlorides ,Glutamates ,Internal medicine ,Protein Phosphatase 1 ,medicine ,Premovement neuronal activity ,Animals ,Gene Knock-In Techniques ,Phosphorylation ,gamma-Aminobutyric Acid ,Multidisciplinary ,Symporters ,Glutamate receptor ,Biological Sciences ,Molecular biology ,Endocytosis ,Endocrinology ,nervous system ,Mutation ,Mutant Proteins ,medicine.symptom ,medicine.drug - Abstract
The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.
- Published
- 2015
123. Schizophrenia drug discovery and development in an evolving era: are new drug targets fulfilling expectations?
- Author
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Nicholas J. Brandon and John Dunlop
- Subjects
Drug ,alpha7 Nicotinic Acetylcholine Receptor ,medicine.drug_class ,media_common.quotation_subject ,Atypical antipsychotic ,Biology ,Glutamatergic ,Drug Delivery Systems ,Glycine Plasma Membrane Transport Proteins ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Humans ,Pharmacology (medical) ,media_common ,Pharmacology ,Drug discovery ,Phosphoric Diester Hydrolases ,Dopaminergic ,medicine.disease ,Psychiatry and Mental health ,Receptors, Glutamate ,Schizophrenia ,Metabotropic glutamate receptor 2 ,Neuroscience ,Antipsychotic Agents - Abstract
Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.
- Published
- 2015
124. A Cell-Based Ultra-High-Throughput Screening Assay for Identifying Inhibitors of D-Amino Acid Oxidase
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Clare Leech, Edward M. Scolnick, Jonathan Schneeweis, Chi-Sung Chiu, Wei Zheng, Philip E. Brandish, Berta Strulovici, Oleg Kornienko, and Nicholas J. Brandon
- Subjects
D-Amino-Acid Oxidase ,High-throughput screening ,Drug Evaluation, Preclinical ,D-amino acid oxidase ,Druggability ,CHO Cells ,Biology ,Transfection ,Models, Biological ,Biochemistry ,Analytical Chemistry ,Automation ,Cricetinae ,Animals ,Humans ,Enzyme Inhibitors ,Receptor ,chemistry.chemical_classification ,Chinese hamster ovary cell ,Small molecule ,Enzyme ,chemistry ,Tissue Array Analysis ,Molecular Medicine ,Biotechnology - Abstract
Enzymes are often considered less "druggable" targets than ligand-regulated proteins such as G-protein-coupled receptors, ion channels, or other hormone receptors. Reasons for this include cellular location (intracellular vs. cell surface), typically lower affinities for the binding of small molecules compared to ligand-specific receptors, and binding (catalytic) sites that are often charged or highly polar. A practical drawback to the discovery of compounds targeting enzymes is that screening of compound libraries is typically carried out in cell-free activity assays using purified protein in an inherently artificial environment. Cell-based assays, although often arduous to design for enzyme targets, are the preferred discovery tool for the screening of large compound libraries. The authors have recently described a novel cell-based approach to screening for inhibitors of a phosphatase enzyme and now report on the development and implementation of a homogeneous 3456-well plate assay for D-amino acid oxidase (DAO). Human DAO was stably expressed in Chinese hamster ovary (CHO) cells, and its activity was measured as the amount of hydrogen peroxide detected in the growth medium following feeding the cells with D-serine. In less than 12 weeks, the authors proved the concept in 96-and then 384-well formats, miniaturized the assay to the 3456-well (nanoplate) scale, and screened a library containing more than 1 million compounds. They have identified several cell-permeable inhibitors of DAO from this cell-based high-throughput screening, which provided the discovery program with a few novel and attractive lead structures.
- Published
- 2006
125. Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia
- Author
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Rosa L. Fradley, E.J. Armstrong, Chi-Sung Chiu, R.B. Heavens, Nicholas J. Brandon, A.R. Rutter, Richard J. Newman, R. Konno, Peter H. Hutson, and Sarah Almond
- Subjects
D-Amino-Acid Oxidase ,Male ,Reflex, Startle ,Mutant ,Phencyclidine ,Mice, Inbred Strains ,Motor Activity ,Quinolones ,Biology ,Serine ,Mice ,Cellular and Molecular Neuroscience ,Sex Factors ,In vivo ,mental disorders ,Reaction Time ,Extracellular ,Animals ,Cyclic GMP ,Molecular Biology ,Swimming ,Brain Chemistry ,Mice, Knockout ,Neurologic Examination ,chemistry.chemical_classification ,Oxidase test ,Dose-Response Relationship, Radiation ,Extremities ,Neural Inhibition ,Cell Biology ,Molecular biology ,Amino acid ,Disease Models, Animal ,Acoustic Stimulation ,nervous system ,chemistry ,Biochemistry ,Glycine ,Schizophrenia ,NMDA receptor ,Female ,Excitatory Amino Acid Antagonists ,Psychomotor Performance - Abstract
d -Amino acid oxidase (DAO) degrades d -serine, a co-agonist at the NMDA receptor (NMDAR). Hypofunction of the NMDAR has been suggested to contribute to the pathophysiology of schizophrenia. Intriguingly, DAO has been recently identified as a risk factor for schizophrenia through genetic association studies. A naturally occurring mouse strain (ddY/DAO−) has been identified which lacks DAO activity. We have characterized this strain both behaviorally and biochemically to evaluate DAO as a target for schizophrenia. We have confirmed that this strain lacks DAO activity and shown for the first time it has increased occupancy of the NMDAR glycine site due to elevated extracellular d -serine levels and has enhanced NMDAR function in vivo. Furthermore, the ddY/DAO− strain displays behaviors which suggest that it will be a useful tool for evaluation of the clinical benefit of DAO inhibition in schizophrenia.
- Published
- 2006
126. Organization of TNIK in dendritic spines
- Author
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Alain C, Burette, Kristen D, Phend, Susan, Burette, Qingcong, Lin, Musen, Liang, Gretchen, Foltz, Noël, Taylor, Qi, Wang, Nicholas J, Brandon, Brian, Bates, Michael D, Ehlers, and Richard J, Weinberg
- Subjects
Neurons ,Dendritic Spines ,Brain ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Article ,Choline O-Acetyltransferase ,Mice, Inbred C57BL ,Mice ,Gene Expression Regulation ,Vesicular Glutamate Transport Protein 1 ,Animals ,Microscopy, Immunoelectron ,gamma-Aminobutyric Acid - Abstract
Tumor necrosis factor receptor-associated factor 2 (TRAF2)- and noncatalytic region of tyrosine kinase (NCK)-interacting kinase (TNIK) has been identified as an interactor in the psychiatric risk factor, Disrupted in Schizophrenia 1 (DISC1). As a step toward deciphering its function in the brain, we performed high-resolution light and electron microscopic immunocytochemistry. We demonstrate here that TNIK is expressed in neurons throughout the adult mouse brain. In striatum and cerebral cortex, TNIK concentrates in dendritic spines, especially in the vicinity of the lateral edge of the synapse. Thus, TNIK is highly enriched at a microdomain critical for glutamatergic signaling.
- Published
- 2014
127. DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling
- Author
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M. Pat Malloy, Jean-Christophe Rain, Nicholas J. Brandon, Sheila Christie, Elaine Huston, Douglas Blackwood, Elaine V. Hill, Sebastienne R. Buchanan, Jennifer E. Chubb, Shaun Mackie, David J. Porteous, L. Miguel Camargo, Walter J. Muir, Rachel James, George S. Baillie, Benjamin S. Pickard, J. Kirsty Millar, Paul J. Whiting, Miles D. Houslay, and Pippa A. Thomson
- Subjects
Adult ,Affective Disorders, Psychotic ,Male ,Candidate gene ,medicine.medical_specialty ,Psychosis ,Nerve Tissue Proteins ,Biology ,Translocation, Genetic ,Cell Line ,DISC1 ,PDE4B ,Gene interaction ,Internal medicine ,Cyclic AMP ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Multidisciplinary ,NDEL1 ,Phosphodiesterase ,Cadherins ,medicine.disease ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Rats ,Cell biology ,Enzyme Activation ,Endocrinology ,3',5'-Cyclic-AMP Phosphodiesterases ,Chromosomes, Human, Pair 1 ,Schizophrenia ,biology.protein ,Chromosomes, Human, Pair 16 ,Protein Binding ,Signal Transduction - Abstract
The disrupted in schizophrenia 1 ( DISC1 ) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B ( PDE4B ) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3′,5′-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
- Published
- 2005
128. Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site
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J. K. Millar, B. Duran-Jimeniz, Nicholas J. Brandon, David J. Porteous, E.J. Handford, Paul J. Whiting, I. Schurov, L.M. Camargo, Paul Hunt, and Mark S. Shearman
- Subjects
Molecular Sequence Data ,Nerve Tissue Proteins ,Mitochondrion ,Biology ,Mice ,Cellular and Molecular Neuroscience ,DISC1 ,Protein structure ,Animals ,Humans ,Amino Acid Sequence ,Nuclear export signal ,Molecular Biology ,Cells, Cultured ,Mitochondrial transport ,Cerebral Cortex ,Genetics ,Binding Sites ,Colocalization ,Cell Biology ,Mitochondria ,Protein Structure, Tertiary ,Cell biology ,Mutation ,biology.protein ,Carrier Proteins ,FEZ1 ,HeLa Cells ,Protein Binding ,Subcellular Fractions ,Binding domain - Abstract
Disrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central coiled-coil region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness.
- Published
- 2005
129. DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness
- Author
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J. Kirsty Millar, Pippa A. Thomson, Nicholas J. Brandon, and Rachel James
- Subjects
Psychosis ,medicine.medical_specialty ,Translocation Breakpoint ,Nerve Tissue Proteins ,Chromosomal translocation ,Linkage Disequilibrium ,Translocation, Genetic ,DISC1 ,DISC2 ,Molecular genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Psychiatry ,Genetics ,biology ,Mood Disorders ,Chromosomes, Human, Pair 11 ,Tumor Suppressor Proteins ,Brain ,General Medicine ,medicine.disease ,DNA-Binding Proteins ,Mood disorders ,Chromosomes, Human, Pair 1 ,Schizophrenia ,biology.protein ,RNA, Long Noncoding ,Carrier Proteins - Abstract
A balanced (1;11)(q42;q14) translocation co-segregates with schizophrenia and major affective disorders in a large Scottish family. The translocation breakpoint on chromosome 1 is located within the Disrupted in Schizophrenia 1 and 2 genes (DISC1 and DISC2). Consequently loss of normal function of these genes is likely to underlie the susceptibility to developing psychiatric disorders that is conferred by inheritance of the translocation. Additionally, a number of independent genetic studies highlight the region of chromosome 1q containing DISC1 and DISC2 as a likely susceptibility locus for both schizophrenia and affective disorders. These genes are thus implicated in the aetiology of major psychiatric disorders in several populations. Although the function of DISC1 was initially unknown, several recent reports have made significant progress towards understanding its role in the central nervous system. Intriguingly, all data obtained to date point towards an involvement in processes critical to neurodevelopment and function. DISC2 has not been studied in detail, but is likely to modulate DISC1 expression. Overall, it is clear from the combination of genetic and functional data that DISC1 and/or DISC2 are emerging as important factors in the molecular genetics of psychiatric illness.
- Published
- 2004
130. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
- Author
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B. Duran-Jimeniz, Paul J. Whiting, E.J. Handford, K.R Oliver, Mark S. Shearman, J.-C Rain, M Pelling, Nicholas J. Brandon, I. Schurov, L.M. Camargo, and Dirk Beher
- Subjects
Leucine zipper ,Macromolecular Substances ,Lissencephaly ,Nerve Tissue Proteins ,Microtubules ,Translocation, Genetic ,Mice ,Cellular and Molecular Neuroscience ,DISC1 ,Cell Movement ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Binding site ,Molecular Biology ,Gene ,Leucine Zippers ,Binding Sites ,NDEL1 ,biology ,Serine Endopeptidases ,Brain ,Gene Expression Regulation, Developmental ,Cell Biology ,medicine.disease ,Protein Structure, Tertiary ,Centrosome ,Schizophrenia ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,Mutation ,biology.protein ,Microtubule-Associated Proteins ,Neuroscience ,Protein Binding - Abstract
Disrupted In Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISC1 interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISC1 and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISC1-Nudel complex as a neurodevelopmental cause of schizophrenia.
- Published
- 2004
131. A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABAA receptors by cAMP-dependent protein kinase via selective interaction with receptor β subunits
- Author
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Marcie Colledge, Stephen J. Moss, Josef T. Kittler, John D Scott, Nicholas J. Brandon, Julia M. Brandon, and Jasmina N. Jovanovic
- Subjects
Macromolecular Substances ,Synaptic Membranes ,A Kinase Anchor Proteins ,Tropomyosin receptor kinase B ,Biology ,Hippocampus ,Synaptic Transmission ,Tropomyosin receptor kinase C ,GABAA-rho receptor ,Cellular and Molecular Neuroscience ,Fetus ,Enzyme-linked receptor ,Animals ,5-HT5A receptor ,Phosphorylation ,Protein kinase A ,Molecular Biology ,gamma-Aminobutyric Acid ,Adaptor Proteins, Signal Transducing ,Binding Sites ,GABAA receptor ,Brain ,Neural Inhibition ,Cell Biology ,Receptors, GABA-A ,Cyclic AMP-Dependent Protein Kinases ,Protein Structure, Tertiary ,Rats ,Cell biology ,Protein Subunits ,COS Cells ,Mutation ,Synapses ,Carrier Proteins ,Cys-loop receptors - Abstract
GABA(A) receptors, the key mediators of fast synaptic inhibition in the brain, are predominantly constructed from alpha(1-6), beta(1-3), gamma(1-3), and delta subunit classes. Phosphorylation by cAMP-dependent protein kinase (PKA) differentially regulates receptor function dependent upon beta subunit identity, but how this kinase is selectively targeted to GABA(A) receptor subtypes remains unresolved. Here we establish that the A-kinase anchoring protein 150 (AKAP150), directly binds to the receptor beta1 and beta3, but not to alpha1, alpha2, alpha3, alpha6, beta2, gamma2, or delta subunits. Furthermore, AKAP79/150 is critical for PKA-mediated phosphorylation of the receptor beta3 subunit. Together, our observations suggest a mechanism for the selective targeting of PKA to GABA(A) receptor subtypes containing the beta1 or beta3 subunits dependent upon AKAP150. Therefore, the selective interaction of beta subunits with AKAP150 may facilitate GABA(A) receptor subtype-specific functional modulation by PKA activity which may have profound local effects on neuronal excitation.
- Published
- 2003
132. Receptor for Activated C Kinase-1 Facilitates Protein Kinase C-Dependent Phosphorylation and Functional Modulation of GABAAReceptors with the Activation of G-Protein-Coupled Receptors
- Author
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Trevor G. Smart, Stephen J. Moss, Jasmina N. Jovanovic, and Nicholas J. Brandon
- Subjects
Macromolecular Substances ,Receptors, Cell Surface ,Immune receptor ,Kidney ,Receptors for Activated C Kinase ,GABAA-rho receptor ,Rats, Sprague-Dawley ,GTP-Binding Proteins ,Animals ,Humans ,ARTICLE ,Phosphorylation ,Receptor ,Cells, Cultured ,Protein Kinase C ,Protein kinase C ,G protein-coupled receptor ,Neurons ,Binding Sites ,Chemistry ,General Neuroscience ,Receptor for activated C kinase 1 ,Receptor Cross-Talk ,Receptors, GABA-A ,Receptors, Muscarinic ,Protein Structure, Tertiary ,Rats ,Cell biology ,Isoenzymes ,Protein Subunits ,nervous system ,Signal transduction ,Protein Binding ,Signal Transduction ,Cys-loop receptors - Abstract
GABA(A) receptors are the principal sites of fast synaptic inhibition in the brain. These receptors are hetero-pentamers that can be assembled from a number of subunit classes: alpha(1-6), beta(1-3), gamma(1-3), delta(1), epsilon, theta;, and pi, but the majority of receptor subtypes is believed, however, to be composed of alpha, beta, and gamma2 subunits. A major mechanism for modulating GABA(A) receptor function occurs via the phosphorylation of residues within the intracellular domains of receptor subunits by a range of serine/threonine and tyrosine kinases. However, how protein kinases are targeted to these receptors to facilitate functional modulation remains unknown. Here we demonstrate that the receptor for activated C kinase (RACK-1) and protein kinase C (PKC) bind to distinct sites on GABA(A) receptor beta subunits. Although RACK-1 is not essential for PKC binding to GABA(A) receptor beta subunits, it enhances the phosphorylation of serine 409, a residue critical for the phospho-dependent modulation of GABA(A) receptor function in the beta1 subunit by anchored PKC. Furthermore, RACK-1 also enhances GABA(A) receptor functional modulation in neurons by a PKC-dependent signaling pathway with the activation of muscarinic acetylcholine receptors (mAChRs). This PKC-dependent modulation of neuronal GABA(A) receptors was mirrored by an increase in the phosphorylation of GABA(A) receptor beta subunits with the activation of mAChRs. Our results suggest a central role for RACK-1 in potentiating PKC-dependent phosphorylation and functional modulation of GABA(A) receptors. Therefore, RACK-1 will enhance functional cross talk between GABA(A) receptors and G-protein-coupled receptors and therefore may have profound effects on neuronal excitability.
- Published
- 2002
133. The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review
- Author
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Tarik Dahoun, Carsten Korth, Svenja V. Trossbach, Nicholas J. Brandon, Oliver D. Howes, and Commission of the European Communities
- Subjects
0301 basic medicine ,Dopamine ,Dopamine Plasma Membrane Transport Proteins ,Review ,Nucleus Accumbens ,Mice ,0302 clinical medicine ,MOUSE MODELS ,Dopamine Uptake Inhibitors ,BEHAVIORAL DEFICITS ,Psychiatry ,biology ,Dopaminergic ,3. Good health ,Psychiatry and Mental health ,Dopamine receptor ,DEPRESSED-PATIENTS ,Psychology ,Life Sciences & Biomedicine ,Locomotion ,medicine.drug ,GENETIC RISK-FACTOR ,Tyrosine 3-Monooxygenase ,INDUCED LOCOMOTOR-ACTIVITY ,NUCLEUS-ACCUMBENS ,Nerve Tissue Proteins ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,POSITRON-EMISSION-TOMOGRAPHY ,Dopamine receptor D2 ,medicine ,Animals ,Amphetamine ,MUTANT MICE ,Biological Psychiatry ,Dopamine transporter ,Science & Technology ,Receptors, Dopamine D2 ,Receptors, Dopamine D1 ,Rats ,030104 developmental biology ,biology.protein ,PROGENITOR PROLIFERATION ,MAJOR MENTAL-ILLNESS ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia.
- Published
- 2017
134. A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing
- Author
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Brian Dougherty, Thomas A. Lanz, D. H. R. Blackwood, D. St Clair, Baohong Zhang, A Power, Stephanie Hall, R Kleiman, Wen He, Stephen M. Lawrie, Sara A. Paciga, Andrew M. McIntosh, XiaoSu Hu, Siby John, W Liu, and Nicholas J. Brandon
- Subjects
Male ,Candidate gene ,dbSNP ,Adolescent ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Cellular and Molecular Neuroscience ,Humans ,Rare functional variant ,Age of Onset ,Letter to the Editor ,Molecular Biology ,Exome ,Genetic Association Studies ,Exome sequencing ,Genetics ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,United Kingdom ,United States ,Minor allele frequency ,Psychiatry and Mental health ,Case-Control Studies ,Schizophrenia ,Female - Abstract
The genetic architecture of schizophrenia is likely contributed by both common and rare variants.1 Recent genome-wide studies have revealed that common variants in the major histocompatibility complex (MHC) region, TCF4 and other genes are associated with schizophrenia.1 In addition, rare copy-number variation (CNV) regions in broad regions like 1q21.1, 15q13.3, 15q11.2, 22q111 as well as individual genes such as Neurexin2, 3 have been identified. Unbiased exome or whole genome scanning procedures have the potential to identify novel loci while likely requiring large sample sets to reach a genome-wide significance level. It is possible that the previously identified genes/regions from high-throughput single-nucleotide polymorphisms (SNP) chip genome-wide scanning techniques, in contrast to some ‘classical' candidate genes,4 may harbor rare coding variants that have a role in disease risk. We selected a total of 101 genes from within the 1q21.1, 15q13.3, 22q11 and 15q11.2 regions and a number of other candidate genes, with either a priori knowledge for association with schizophrenia, for example, TCF4/CCDC68, NRXN1, or interesting for drug-discovery efforts, for example, cyclic nucleotide phosphodiesterase genes, and surveyed rare variants in their coding regions through deep sequencing. Our sample set included cases who met DSM-IV criteria for schizophrenia. All subjects provided informed consent that was approved by the ethics committees at the specific sites. Our discovery set included 525 schizophrenia cases (68% male cases, 69 cases were diagnosed with schizophrenia before 18 years of age) and 619 controls (62% male cases) without any neurological and psychiatric disorders and were primarily collected during Pfizer clinical trials. The replication set includes 455 schizophrenia subjects (71% male subjects) and 336 controls (73.5% male subjects), collected at the Universities of Edinburgh and Aberdeen. Only Caucasian subjects were included in our study to reduce the sample heterogeneity. Coding sequences in our target regions were enriched using the Nimblegen capture array, followed by Illumina HiSeq paired-end sequencing at the Beijing Genome Institute (BGI Inc.). We pooled 48 bar-coded samples together before the sequencing run. In total, we obtained 149 Mb of sequencing data in which over 98.5% of reads mapped to our regions of interest. The mean read depth was 96 × , which is much higher than the estimated average depth (33 × ) required for highly accurate downstream heterozygous variant detection. After removing genes with low coverage that failed the capture design, over 95.3% of the bases in our targeted regions were covered with genotype data at least 30 × to ensure variant detection sensitivity. The variants have a greater than 99.6% concordance rate with available genome-wide genotyping data. A total of 7072 and 5170 novel variants were identified in the discovery and replication sets, respectively (we excluded all Indel calls, which may have a higher false-positive rate). Approximately, 70% of the variants are not common in the population (minor allele frequency number no greater than 1%). In both data sets, we found a variety of SNPs including intronic, missense, synonymous and UTR variants as well as splice variants and nonsense SNPs (Table 1). We observed approximately two fold rare (minor allele frequency number greater than 0.5%) nonsense alleles in cases compared with the nonsense alleles in controls (one-sided P-value=0.056, odd ratio (OR)=1.96). In contrast, we observed about equal frequencies of rare synonymous variants in cases and controls in the identical genomic regions for the same cohorts (one-sided P>0.1, OR=1.08), suggesting that it is unlikely that the result is due to sampling bias. Furthermore, the proportion of ultra-rare ‘deleterious' variants in the CNV regions is significantly higher in early-onset schizophrenia cases (age of onset less than 18 years) versus that in the controls in the study (nonsense plus splicing one-sided P-value=0.09, OR=3.41; including conserved damaging missense variants: one-sided P=0.02, OR=1.88), supporting the finding that rare variants may contribute to schizophrenia etiology. None of the rare nonsense variants identified in this study were listed in dbSNP (version 132). Intriguingly, different stop codons in NRXN1 were observed in two individuals with schizophrenia from two independent cohorts but were not observed in any of the controls, suggesting that rare loss-of-function events in NRXN1, either through deletion or through nonsense mutation, could be important in the etiology of schizophrenia (Supplementary Table S1). Table 1 Variants identified in the two independent cohorts Most of the rare variants only occur once or twice in our cohort, which limits the statistical power to detect the association in individual variants. We therefore conducted aggregate analysis across all functional variants within each gene by comparing carrier frequencies between cases and controls to understand whether the gene as a whole has a consistent effect across the discovery and replication data sets. We focused on functional variants with a minor allele frequency no higher than 1% in controls in our analysis. Among the 84 genes with at least one rare functional variant tested in both sample sets, 48 genes showed a consistent pattern of frequency distribution (Supplementary Table S2) although none of these associations passed the multiple test correction. Among these 48 genes, a majority of genes (30) showed an elevated frequency of rare variants in cases compared with controls, including the TCF4 gene. Common SNPs in TCF4 have emerged from the schizophrenia genome-wide association study (GWAS) consortia and confirmed to be associated, at genome-wide levels of significance, with the disease risk1, 5. Furthermore, one of the SNPs (rs9960767) has been linked to deficits in sensorimotor gating,6 and the expression levels of TCF4 were shown to be increased in patients with psychosis7 and be under the regulation of the schizophrenia-linked miRNA-137.8 Rare mutations in TCF4 have been previously identified in autosomal dominant forms of the Pitt–Hopkins syndrome, a disorder characterized by severe motor and mental retardation and susceptibility to childhood-onset seizures.9 A total of seven distinct rare functional variants in TCF4 were identified in our two cohorts; intriguingly, they do not overlap with the known Pitt–Hopkins-associated variants (Supplementary Table S3). Three different variants were identified in the discovery cohort, with one variant (chr18:52928743:G_A) carried by three sporadic schizophrenia cases. Five variants occurred in the replication cohort and they all appeared in cases. The variant chr18:52928743:G_A is observed in a total of five schizophrenia cases and one control across the two cohorts. The same variant has a consistently rare frequency in the large general population (9/6494 from the Exome Variant server; 1/947 in our controls) and is lower than what we observed in the schizophrenia subjects (5/922). TCF4 is a complex gene with multiple transcripts with variation in their N-termini.10 The C terminus is shared between variants with a conserved basic helix-loop-helix domain, which is critical for dimerization (homo-, hetero-), DNA binding at Eprussi box (E-box) sequences and transcriptional activation. Intriguingly, Pitt–Hopkins mutations congregate in these C-terminal domains and have been shown to differentially impact these functions. The mutations we have identified are principally in the N-terminal domains, and depending on the different exons spliced into a specific transcript these may have impact on processes such as subcellular localization as well as protein–protein and protein–DNA interactions. Although beyond the scope of this work, it will be important to understand the functional impact of these identified variants in the context of transcripts expressed in the schizophrenic brain. In summary, the study suggests that the current candidate genes obtained from unbiased GWAS and CNV scanning reports do harbor rare functional variants in sporadic schizophrenia patients. We observed an overall enrichment for damaging variants, especially nonsense variants. In particular, a similar effect was observed in early-onset cases. Together, this supports our hypothesis that rare coding (for example, loss of function) variants in deletion/SNP regions from previous genome-wide scanning reports may also contribute to the genetic architecture of schizophrenia. The sample sizes in the study limit our ability to pinpoint specific genes/variants but the identified variants, especially in NXRN1 and TCF4, will be helpful in future functional genomic investigations of the genes and related biological pathways.
- Published
- 2014
135. Cyclic-Nucleotide Phosphodiesterases In The Central Nervous System
- Author
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Nicholas J. Brandon and Anthony R. West
- Subjects
medicine.anatomical_structure ,Central nervous system ,medicine ,Biology ,Cyclic nucleotide phosphodiesterases ,Cell biology - Published
- 2014
136. Molecular And Cellular Understanding of PDE10A: A Dual-Substrate Phosphodiesterase with Therapeutic Potential to Modulate Basal Ganglia Function
- Author
-
Nicholas J. Brandon and Erik I. Charych
- Subjects
Chemistry ,Basal ganglia ,Phosphodiesterase ,Substrate (chemistry) ,PDE10A ,Striatum ,Neuroscience ,Function (biology) - Published
- 2014
137. Emerging Role for PDE4 in Neuropsychiatric Disorders: Translating Advances from Genetic Studies Into Relevant Therapeutic Strategies
- Author
-
Akira Sawa, Sandra Zoubovsky, and Nicholas J. Brandon
- Subjects
medicine.medical_specialty ,Psychotherapist ,Huntington's disease ,business.industry ,Schizophrenia (object-oriented programming) ,Medicine ,business ,Psychiatry ,medicine.disease ,Depression (differential diagnoses) - Published
- 2014
138. Wiley Series in Drug Discovery and Development
- Author
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Nicholas J. Brandon and Anthony R. West
- Subjects
Series (mathematics) ,Computer science ,Drug discovery ,Computational biology - Published
- 2014
139. Constitutive tyrosine phosphorylation of the GABAA receptor γ2 subunit in rat brain
- Author
-
J. Hill, Nicholas J. Brandon, Trevor G. Smart, Stephen J. Moss, and P Delmas
- Subjects
Intracellular Fluid ,Guinea Pigs ,Molecular Sequence Data ,Protein tyrosine phosphatase ,SH2 domain ,Receptor tyrosine kinase ,Cell Line ,GABAA-rho receptor ,Rats, Sprague-Dawley ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Antibody Specificity ,Animals ,Humans ,Amino Acid Sequence ,Phosphorylation ,Cells, Cultured ,Cerebral Cortex ,Neurons ,Pharmacology ,biology ,Immune Sera ,Brain ,Tyrosine phosphorylation ,Embryo, Mammalian ,Phosphoproteins ,Receptors, GABA-A ,Protein Structure, Tertiary ,Rats ,src-Family Kinases ,chemistry ,Biochemistry ,ROR1 ,biology.protein ,Tyrosine ,Rabbits ,Platelet-derived growth factor receptor ,Protein Binding ,Proto-oncogene tyrosine-protein kinase Src - Abstract
GABA(A) receptors are the major sites of fast synaptic inhibition in the brain, where they are predominantly composed of alpha, beta and gamma2 subunits. A role for direct tyrosine phosphorylation of residues 365 and 367 (Y365/367) within the intracellular domain of the gamma2 subunit has been suggested to be important in modulating GABA(A) receptor function, based on the study of recombinant receptors. To address the relevance of these observations for neuronal GABA(A) receptors we have studied the phosphorylation of the gamma2 subunit in the brain. In adult rat brain the gamma2 subunit is phosphorylated on tyrosine residues, including Y365/367 as defined using a phosphospecific antisera. In cultured cortical neurones, phosphorylation of Y365/367 is highly regulated and was only evident upon inhibition of tyrosine phosphatases. We also establish that the tyrosine kinase Src is capable of specifically interacting with the intracellular domains of receptor beta and gamma2 subunits. This may specifically localise tyrosine kinase activity to GABA(A) receptors, facilitating rapid receptor tyrosine phosphorylation upon kinase activation. Together our results suggests that tyrosine phosphorylation of the gamma2 subunit, possibly by closely associated Src, may be a dynamic mechanism for regulating GABA(A) receptor function in the brain.
- Published
- 2001
140. Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons
- Author
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Nicholas J. Brandon, Josef T. Kittler, Talia A. Atkin, and Andrew F. MacAskill
- Subjects
Time Factors ,Phenylalanine ,Schizophrenia (object-oriented programming) ,Nerve Tissue Proteins ,Mitochondrion ,Transfection ,Hippocampus ,behavioral disciplines and activities ,Cellular and Molecular Neuroscience ,DISC1 ,Leucine ,mental disorders ,Animals ,Humans ,RNA, Small Interfering ,Molecular Biology ,Cells, Cultured ,Neurons ,Polymorphism, Genetic ,biology ,Axons ,Mitochondria ,Rats ,Cell biology ,Luminescent Proteins ,Protein Transport ,Psychiatry and Mental health ,Animals, Newborn ,Gene Expression Regulation ,nervous system ,Mutation ,biology.protein ,Neuroscience ,Intracellular - Abstract
Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons
- Published
- 2010
141. Cell Surface Stability of γ-Aminobutyric Acid Type A Receptors
- Author
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Trevor G. Smart, Philip Thomas, Josef T. Kittler, Julia M. Uren, Stephen J. Moss, Nicholas J. Brandon, and Christopher N. Connolly
- Subjects
Receptor recycling ,Neurotransmitter receptor ,Cell surface receptor ,Enzyme-linked receptor ,Cell Biology ,Immune receptor ,Signal transduction ,Biology ,Receptor ,Molecular Biology ,Biochemistry ,Cell biology ,Cys-loop receptors - Abstract
Type A gamma-aminobutyric acid receptors (GABA(A)), the major sites of fast synaptic inhibition in the brain, are believed to be composed predominantly of alpha, beta, and gamma subunits. Although cell surface expression is essential for GABA(A) receptor function, little is known regarding its regulation. To address this issue, the membrane stability of recombinant alpha(1)beta(2) or alpha(1)beta(2)gamma(2) receptors was analyzed in human embryonic kidney cells. Alpha(1)beta(2)gamma(2) but not alpha(1)beta(2) receptors were found to recycle constitutively between the cell surface and a microtubule-dependent, perinuclear endosomal compartment. Similar GABA(A) receptor endocytosis was also seen in cultured hippocampal and cortical neurons. GABA(A) receptor surface levels were reduced upon protein kinase C (PKC) activation. Like basal endocytosis, this response required the gamma(2) subunit but not receptor phosphorylation. Although inhibiting PKC activity did not block alpha(1)beta(2)gamma(2) receptor endocytosis, it did prevent receptor down-regulation, suggesting that PKC activity may block alpha(1)beta(2)gamma(2) receptor recycling to the cell surface. In agreement with this observation, blocking recycling from endosomes with wortmannin selectively reduced surface levels of gamma(2)-containing receptors. Together, our results demonstrate that the surface stability of GABA(A) receptors can be dynamically and specifically regulated, enabling neurons to modulate cell surface receptor number upon the appropriate cues.
- Published
- 1999
142. GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton
- Author
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Stephen J. Moss, Richard W. Olsen, FK Bedford, Nicholas J. Brandon, and Hongbing Wang
- Subjects
Adult ,DNA, Complementary ,Recombinant Fusion Proteins ,GABARAP ,Molecular Sequence Data ,Gene Expression ,Class C GPCR ,Saccharomyces cerevisiae ,Biology ,Rhodopsin-like receptors ,GABAA-rho receptor ,Fetus ,Tubulin ,Neurotransmitter receptor ,Animals ,Humans ,Tissue Distribution ,Amino Acid Sequence ,Cloning, Molecular ,Receptor ,Cells, Cultured ,Cytoskeleton ,Adaptor Proteins, Signal Transducing ,Glutathione Transferase ,Multidisciplinary ,Base Sequence ,GABAA receptor ,Biological Transport ,Receptors, GABA-A ,Rats ,Cell biology ,Biochemistry ,Apoptosis Regulatory Proteins ,Microtubule-Associated Proteins ,Protein Binding ,Cys-loop receptors - Abstract
Type-A receptors for the neurotransmitter GABA (gamma-aminobutyric acid) are ligand-gated chloride channels that mediate inhibitory neurotransmission. Each subunit of the pentameric receptor protein has ligand-binding sites in the amino-terminal extracellular domain and four membrane-spanning regions, one of which forms a wall of the ion channel. Each subunit also has a large intracellular loop that may be a target for protein kinases and be required for subcellular targeting and membrane clustering of the receptor, perhaps by anchoring the receptor to the cytoskeleton. Neurotransmitter receptors need to be positioned in high density in the cell membrane at sites postsynaptic to nerve terminals releasing that neurotransmitter. Other members of the superfamily of ligand-gated ion-channel receptors associate in postsynaptic-membrane clusters by binding to the proteins rapsyn or gephyrin. Here we identify a new cellular protein, GABA(A)-receptor-associated protein (GABARAP), which can interact with the gamma2 subunit of GABA(A) receptors. GABARAP binds to GABA(A) receptors both in vitro and in vivo, and co-localizes with the punctate staining of GABA(A) receptors on cultured cortical neurons. Sequence analysis shows similarity between GABARAP and light chain-3 of microtubule-associated proteins 1A and 1B. Moreover, the N terminus of GABARAP is highly positively charged and features a putative tubulin-binding motif. The interactions among GABA(A) receptors, GABARAP and tubulin suggest a mechanism for the targeting and clustering of GABA(A) receptors.
- Published
- 1999
143. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice
- Author
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Atsushi Kamiya, Kozo Kaibuchi, Koko Ishizuka, J K Millar, M Morita, Weidong Li, C Hookway, D.R. Weinberger, David J. Porteous, Tyrone D. Cannon, Alcino J. Silva, John C. Roder, Nicholas J. Brandon, Shinichiro Taya, Steven J. Clapcote, Akira Sawa, Toshifumi Tomoda, Yanxun Xu, Jingshan Chen, Barbara K. Lipska, and Mikhail V. Pletnikov
- Subjects
Gene isoform ,Genetics ,biology ,Gene Expression ,Nerve Tissue Proteins ,C57bl 6j ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Mice ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,DISC1 ,Species Specificity ,biology.protein ,Animals ,Protein Isoforms ,Molecular Biology - Abstract
Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice
- Published
- 2007
144. The cellular target of antidepressants
- Author
-
Ronald D.G. McKay and Nicholas J. Brandon
- Subjects
Fluoxetine ,Drug discovery ,General Neuroscience ,Dentate gyrus ,Neurogenesis ,Pharmacology ,Biology ,medicine ,Antidepressant ,Endocrine effects ,Serotonin ,Receptor ,Neuroscience ,medicine.drug - Abstract
The serotonin 1A receptor expressed on mature granule cells in the dentate gyrus mediates the behavioral, neurogenic and endocrine effects of the antidepressant fluoxetine in the mouse.
- Published
- 2015
145. Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system
- Author
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Andrew D, Randall, Mai, Kurihara, Nicholas J, Brandon, and Jon T, Brown
- Subjects
Cerebral Cortex ,psychiatric genetics ,synaptic plasticity ,Mental Disorders ,elecrtophysiology ,synaptic physiology ,Animals ,Humans ,Nerve Tissue Proteins ,Special Issue: Synaptic Basis of Disease ,neurophysiology ,Hippocampus ,Synaptic Transmission - Abstract
The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.
- Published
- 2013
146. The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor γ2 subunit
- Author
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Rochelle M. Hines, Maribel Rios, Nicholas J. Brandon, Zhen Yan, Rachel Jurd, Stephen J. Moss, Miho Terunuma, Mansi Vithlani, Dustin J. Hines, Raquel Revilla-Sanchez, Phillip Haydon, and Ping Zhong
- Subjects
medicine.medical_specialty ,Heterozygote ,Neurogenesis ,Mutation, Missense ,Hippocampal formation ,Biology ,Hippocampus ,Mice ,Neurotrophic factors ,Internal medicine ,medicine ,Premovement neuronal activity ,Animals ,Phosphorylation ,Receptor ,Brain-derived neurotrophic factor ,Neurons ,GABAA receptor ,Depression ,General Neuroscience ,Brain-Derived Neurotrophic Factor ,Articles ,Receptors, GABA-A ,Protein Subunits ,Protein Transport ,Endocrinology ,Phenotype ,Inhibitory Postsynaptic Potentials ,Tyrosine - Abstract
Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal activity, neurogenesis, and depressive-like behaviors; however, downstream effectors by which BDNF exerts these varying actions remain to be determined. Here we reveal that BDNF induces long-lasting enhancements in the efficacy of synaptic inhibition by stabilizing γ2 subunit-containing GABAAreceptors (GABAARs) at the cell surface, leading to persistent reductions in neuronal excitability. This effect is dependent upon enhanced phosphorylation of tyrosines 365 and 367 (Y365/7) in the GABAAR γ2 subunit as revealed using mice in which these residues have been mutated to phenyalanines (Y365/7F). Heterozygotes for this mutation exhibit an antidepressant-like phenotype, as shown using behavioral-despair models of depression. In addition, heterozygous Y365/7F mice show increased levels of hippocampal neurogenesis, which has been strongly connected with antidepressant action. Both the antidepressant phenotype and the increased neurogenesis seen in these mice are insensitive to further modulation by BDNF, which produces robust antidepressant-like activity and neurogenesis in wild-type mice. Collectively, our results suggest a critical role for GABAAR γ2 subunit Y365/7 phosphorylation and function in regulating the effects of BDNF.
- Published
- 2013
147. Future viable models of psychiatry drug discovery in pharma
- Author
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Jeremy R. Edgerton, Zoë A. Hughes, Nicholas J. Brandon, and Stacey J. Sukoff Rizzo
- Subjects
Population ageing ,medicine.medical_specialty ,Drug discovery ,Emerging technologies ,Mental Disorders ,Biochemistry ,Analytical Chemistry ,Unmet needs ,Drug Discovery ,Models, Animal ,medicine ,Molecular Medicine ,Animals ,Humans ,Business ,Molecular Targeted Therapy ,Psychiatry ,Biotechnology ,Antipsychotic Agents - Abstract
The unmet need for the treatment of disorders of the nervous system is growing, and as highlighted in the media and elsewhere, the results of an aging population will ensure this continues with an upward trajectory. Incredibly, the efforts within industry to identify new drugs to treat these conditions have seemingly disappeared despite the growing need. There has been a run of extraordinary failure in the later stages of the drug discovery process for neurological and psychiatric disorders, which has many causes. We believe, though, that we have to confront this dire situation, both by using learnings from the post hoc analysis of our historical failure, as well as harnessing the bewildering array of new technologies and data now available to us, to ensure we are making the right decisions along the very complicated path of drug discovery to registration.
- Published
- 2013
148. Novel triazines as potent and selective phosphodiesterase 10A inhibitors
- Author
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Menelas N. Pangalos, James Joseph Erdei, Rudolf Schindler, Thorsten Hage, Christian Grunwald, Hans Stange, Michael S. Malamas, Julie A. Brennan, Barbara Langen, Nicholas J. Brandon, Norbert Hoefgen, Kristi Fan, Yike Ni, Boyd L. Harrison, Albert J. Robichaud, Karen L. Marquis, Radka Graf, Kevin Parris, Hans-Joachim Lankau, Steven M. Grauer, Rachel Navarra, Ute Egerland, and Thomas Kronbach
- Subjects
Drug ,Models, Molecular ,Phosphodiesterase Inhibitors ,media_common.quotation_subject ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,Hyperkinesis ,Crystallography, X-Ray ,Biochemistry ,Structure-Activity Relationship ,Pharmacokinetics ,Drug Discovery ,Potency ,Animals ,Humans ,Molecular Biology ,media_common ,ADME ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Phosphoric Diester Hydrolases ,Triazines ,Organic Chemistry ,Phosphodiesterase ,Bioavailability ,Rats ,Molecular Medicine ,PDE10A ,Dizocilpine Maleate ,Selectivity - Abstract
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
- Published
- 2012
149. Linking neurodevelopmental and synaptic theories of mental illness through DISC1
- Author
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Nicholas J. Brandon and Akira Sawa
- Subjects
medicine.medical_specialty ,Nerve Tissue Proteins ,Models, Biological ,Translocation, Genetic ,Article ,DISC1 ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Psychiatry ,Biological studies ,biology ,Extramural ,General Neuroscience ,Mental Disorders ,Brain ,Gene Expression Regulation, Developmental ,Mental illness ,medicine.disease ,Genetic architecture ,Schizophrenia ,Endophenotype ,Synapses ,biology.protein ,Neuroscience - Abstract
Recent advances in our understanding of the underlying genetic architecture of psychiatric disorders has blown away the diagnostic boundaries that are defined by currently used diagnostic manuals. The disrupted in schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of an inherited chromosomal translocation, which segregates with major mental illnesses. In addition, many biological studies have indicated a role for DISC1 in early neurodevelopment and synaptic regulation. Given that DISC1 is thought to drive a range of endophenotypes that underlie major mental conditions, elucidating the biology of DISC1 may enable the construction of new diagnostic categories for mental illnesses with a more meaningful biological foundation.
- Published
- 2011
150. Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3
- Author
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Douglas Blackwood, Li Sha, Walter J. Muir, Nicholas J. Brandon, J A Machell, M. P. Kelly, Steven J. Clapcote, Lynsey MacIntyre, David J. Porteous, David G. Watson, Benjamin S. Pickard, and University of Strathclyde [Glasgow]
- Subjects
Transcription, Genetic ,SOX transcription factor ,Mice ,chemistry.chemical_compound ,transcriptomics ,0302 clinical medicine ,Basic Helix-Loop-Helix Transcription Factors ,Transcriptional regulation ,SOX Transcription Factors ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Neurons ,bipolar disorder ,0303 health sciences ,biology ,NPAS3 ,Neurogenesis ,glycolysis ,metabolomics ,Circadian Rhythm ,3. Good health ,Psychiatry and Mental health ,medicine.medical_specialty ,Recombinant Fusion Proteins ,Nerve Tissue Proteins ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Transcription factor ,030304 developmental biology ,Dihydroxyacetone phosphate ,Brain Chemistry ,Microarray analysis techniques ,Mice, Inbred C57BL ,schizophrenia ,Metabolic pathway ,HEK293 Cells ,Endocrinology ,chemistry ,Dentate Gyrus ,biology.protein ,Energy Metabolism ,Transcriptome ,Transcription Factor Gene ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients.
- Published
- 2011
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