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This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. [ABSTRACT FROM AUTHOR]

Objective In patients with benign myoclonus epilepsy (ME), giant sensory-evoked potential (SEP) reflects the hyperexcitability of the sensory cortex. The aim of this study was to compare the effect of quadripulse transcranial magnetic stimulation (QPS) on the median nerve SEP between ME patients and healthy subjects. Methods Ten healthy volunteers and six ME patients with giant SEP participated in this study. QPSs at interpulse intervals (IPIs) of 5, 30, 50, 100, 500 and 1250 ms were applied over the left primary motor cortex (M1) for 30 min. The peak-to-peak amplitudes of N20 to P25 (N20–P25) and P25 to N33 (P25–N33) components were measured at the left somatosensory cortex. Results In healthy participants, the P25–N33 was bidirectionally modulated by QPS over M1, following the Bienenstock–Cooper–Munro (BCM) theory. The N20–P25 was not affected by any QPSs. In ME patients, the giant P25–N33 was potentiated after any QPSs. Furthermore, the N20–P25 was also potentiated after QPS at IPIs of 5, 30, 50 100 or 500 ms. Conclusions In ME patients, the cascade for long-term depression-like effects may be impaired. Significance The giant SEP was furthermore enhanced by QPS. [ABSTRACT FROM AUTHOR]

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity.

Long-term synaptic depression (LTD) in cortico-striatal circuits is initiated by depolarization of striatal medium spiny neurons through a convergent cortical glutamatergic input. This produces retrograde endocannabinoid signaling to presynaptic cortical terminals and eventually results in long term (>30 min) decreases in glutamate release. These same circuits can also undergo short-term depression (STD) through a less well-defined process in which the magnitude of postsynaptic responses returns to baseline levels within 10 min. Additionally, the cortico-striatal circuit shows characteristics of a GABA A receptor-dependent low-pass filter, which results in significant attenuation of high frequency cortical inputs. The majority of in vitro studies of LTD have used a 100-Hz induction paradigm and it is unclear whether other frequencies, which may also have physiological relevance, have equivalent ability to induce this form of plasticity. Here we have investigated the effectiveness of a range of induction paradigms in producing LTD in cortico-striatal circuits, and demonstrate that some lower frequency paradigms, with perhaps more physiological relevance, are more effective at inducing LTD. We also show that GABA A receptor-dependent frequency filtering in this circuit is altered following the induction of LTD and STD suggesting an important role for synaptic depression in signal processing in these circuits. [ABSTRACT FROM AUTHOR]

Background Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson’s disease and in l -3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson’s disease. Methods Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. Results We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. Conclusions These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA. [ABSTRACT FROM AUTHOR]

Abstract: Endogenous cannabinoids play important roles in a variety of functions in the mammalian brain, including the regulation reward-related information processing. The primary mechanism through which this is achieved is the presynaptic modulation of synaptic transmission. During reward- and reinforcement-related behavior dopamine levels increase in forebrain areas and this has recently been shown to be modulated by the endocannabinoid system. Therefore, understanding how endocannabinoids are mobilized to modulate synaptic inputs impinging on midbrain dopamine neurons is crucial to a complete understanding of the roles that these molecules play in reward behavior, drug abuse and addiction. Here we summarize the literature describing short-term and long-term regulation of afferent connections on dopamine neurons in the ventral tegmental area via endocannabinoid activation of cannabinoid CB1 receptors, and describe the mechanisms through which these molecules are released during reward-based behavior and exposure to abused drugs. [Copyright &y& Elsevier]

Highlights: [•] Peripheral injection of 5% formalin or CFA induced discharges of the C-fibers. [•] The C-fiber-evoked field potentials induced spinal LTP within 3h. [•] Low- and high-frequency electric stimulation of the sciatic nerve induced spinal LTP. [•] TRPV1 receptor antagonists CPZ or AMG 9810 inhibited the LTP induction. [ABSTRACT FROM AUTHOR]

Highlights: [•] Neuronal nitric oxide synthase is necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia. [•] Episodic spinal NO is sufficient to elicit facilitation of phrenic nerve activity (pMF). [•] NO-induced pMF involves 5-HT2B receptors and spinal NADPH oxidase activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] EPSP–IPSP interaction induces plasticity in convergent excitatory and inhibitory inputs. [•] EPSP–IPSP interaction induces differential modifications in competitive MCs. [•] Plasticity in competitive MCs displays distinct requirements on NMDAR activity. [ABSTRACT FROM AUTHOR]

Abstract: It is known that lipopolysaccharide (LPS) treatment induces neuroinflammation and memory deterioration. One of the mechanisms may be the interference with brain-derived neurotrophic factor (BDNF) gene expression and function. Lipopolysaccharide (3μg/kg and 10μg/kg) was unilaterally injected into the substantia nigra of adult male Wistar rats. Pergolide-induced rotational behavior test was employed to validate unilateral damage to the dopamine nigrostriatal neurons. Anxiety–depression-like behaviors were studied by means of elevated plus-maze task and forced swimming test, as animal models of anxiety and depression. Rats given LPS exhibited the following: decrease of the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming and increase of immobility times within forced swimming test. In addition, these behaviors are associated with decreased BDNF mRNA expression in rat hippocampus. Taken together, these data indicate that intranigral LPS infusion influences the induction of BDNF mRNA expression within hippocampus which contributes to observed behavioral responses in rats, with relevance for Parkinson's disease conditions. [Copyright &y& Elsevier]

Highlights: [•] Actin cytoskeleton and its regulatory proteins are needed for memory formation. [•] Actin cytoskeleton and its regulatory proteins are essential for synaptic plasticity. [•] Actin cytoskeleton is involved in synaptic transmission and neuronal morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction. [Copyright &y& Elsevier]

Highlights: [•] Saturating levels of LTP and LTD were induced in slices of the lateral amygdala. [•] Maximum LTP and LTD determine the extent of the synaptic modification range. [•] Maternal separation stress shrank the modification range in the thalamic input. [•] Maternal separation enhanced LTD in the cortical input. [•] Altered synaptic plasticity will have consequences for amygdala-dependent learning. [ABSTRACT FROM AUTHOR]

Highlights: [•] Can animal models be used for studying affective and cognitive comorbidities of pain? [•] How does pain interact with its comorbidities in the animals? [•] What are the underlying mechanisms of pain comorbidities in the animals? [Copyright &y& Elsevier]

Abstract: Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical ‘α-kinases’. It phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids. The activity of eEF2K is normally dependent on calcium ions and calmodulin. eEF2K is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Recent data show that eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Growing evidence points to roles for eEF2K in neurological processes such as learning and memory and perhaps in depression. [Copyright &y& Elsevier]

Highlights: [•] RanBP9 overexpression decreases dendritic arbor in the cortex and hippocampus. [•] RanBP9 reduced spine density at 12 months of age but not at 6months. [•] Decreased spine density correlated well with the reduced levels of phospho-cofilin. [•] Reduced spine density provided the physical basis for the loss of synaptic proteins. [Copyright &y& Elsevier]

Abstract: While the importance of epigenetic mechanisms is well established for numerous aspects of cell differentiation and development, recent findings have shown epigenetic processes to be a critical regulatory component in postmitotic neurons. Particularly intriguing, and potentially significant, are data demonstrating epigenetic regulation of cognitive behaviors. Different aspects of learning and memory appear to be regulated at the level of epigenetic chromatin modifications. Furthermore, it is becoming clear that the dysfunction of epigenetic mechanisms can lead to various disorders accompanied by significant mental impairment. Here, we review the evidence for the epigenetic control of cognition and the role of epigenetic dysregulation in mental disorders. A better understanding of epigenetic mechanisms will increase our fundamental knowledge of cognition and also provide new and exciting avenues of treatment for various mental disorders. [Copyright &y& Elsevier]

Highlights: [•] Memantine rescued hippocampal-dependent memory and hippocampal LTD in JDM rats. [•] LTD was impaired by a malfunction in NR2B-containing NMDA receptors in JDM rats. [•] Abnormal NMDA receptor function was caused by excessive PKA activity in JDM rats. [Copyright &y& Elsevier]

Highlights: [•] Excitotoxicity is a primary mechanism of neuronal injury following stroke. [•] Excitotoxicity requires influx of calcium ion through the NMDA receptor. [•] Different subpopulations of the NMDA receptor elicit distinct functional output. [•] NMDA receptor promotes neuronal death or survival depending on what's downstream. [•] Studying downstream signaling events allows development of better stroke treatments. [ABSTRACT FROM AUTHOR]

Abstract: A subgroup of anticonvulsant and neuroleptic drugs acts through the potentiation of GABA pathways. The regulatory role of GABA in neuronal circuit formation is related to its depolarizing action that supports activity-dependent synaptogenesis. We hypothesized that elevated levels of GABA in the immature brain modify synaptogenesis in excitatory synapses and consequently affect mice behavior. In support of this theory, we showed previously that neonatal exposure to a GABA-transaminase inhibitor (Vigabatrin, GVG) modifies the expression of presynaptic proteins and suppresses excitatory synaptic potentials. To further characterize this phenomenon, we examined the effect of GVG applied during postnatal days 4–14, during the switch in GABA function from a depolarizing to a hyperpolarizing substance, on the development of excitatory synapses and mice sociability. Early exposure to GVG induced differential effects on synaptic proteins in the hippocampus and the cerebral cortex, including the downregulation of GluR1/GluR2 and NR2A/NR2B ratios in the hippocampus cytoplasm, a minute effect on the regulatory proteins CAMKII and PKA in the cerebral cortex, and increases in pGluR1, CAMKII, PKA and Reelin levels. Early GVG exposure was also associated with region specific regulation of monoamines, reduction in hippocampal DA, and enhancement of cortical NE levels. Age-dependent modified sociability and lack of preference for social interactions were observed in mice treated with GVG. Overall, early life exposure to GVG is expected to alter cortico-hippocampal axis connectivity and balance due to the different effects GVG has on key synaptic proteins in the associated brain regions, thus potentially causing behavioral impairment. [Copyright &y& Elsevier]

Highlights: [•] Ca2+ permeability of synaptic AMPARs can be altered by trafficking events. [•] GluA2-lacking AMPARs are added to synapses following stimulation. [•] This occurs under specific conditions at a subset of synapses in the CNS. [•] Endosomal trafficking and lateral diffusion from perisynaptic regions are involved. [•] AMPAR interacting proteins regulate this process. [Copyright &y& Elsevier]

Highlights: [•] Obesity originates from disturbed neuropsychological functioning. [•] Chronic stress enhances food intake and lowers cerebral energy content. [•] Food intake and stress per se activate the reward circuitry. [•] Stress, neuroenergetic depletion, and reward system activation build a vicious cycle. [•] This vicious cycle induces obesity. [Copyright &y& Elsevier]

Abstract: At synapses, pre- and post-synaptic cells get in direct contact with each other via cell adhesion molecules (CAMs). Several CAMs have been identified at the neuromuscular junction and at central synapses, where they regulate synaptic strength, by recruiting scaffolding proteins, neurotransmitter receptors and synaptic vesicles in response to the binding of counter-receptors across the synaptic cleft. Many synapses are also surrounded by astrocytic processes and embedded in conspicuous extracellular matrix (ECM). It is now widely recognized that astrocytes play a central role in regulating the synaptic machinery by exchanging information with the neuronal elements via diffusible molecules and direct physical interactions; this has lead to the concept of the ‘tri-partite synapse’. More recently, the term ‘tetra-partite synapse’ has been introduced to underlie the importance of ECM in shaping synaptic function by mediating interaction and signaling between neurons and astrocytes. Here, we will review how this integrated view of the synapse can help us understand homeostatic synaptic plasticity at the neuromuscular junction and in the central nervous system. We will explore how synaptic CAMs regulate two forms of homeostatic plasticity: (i) postsynaptic scaling of synaptic currents to counteract changes in neuronal network activity and (ii) the compensatory modulation of presynaptic neurotransmitter release in response to changes in postsynaptic efficacy. We will discuss recent findings on activity-dependent trans-synaptic signaling events and the role of cell adhesion in the feedback control of network activity. This article is part of the Special Issue entitled ‘Homeostatic Synaptic Plasticity’. [Copyright &y& Elsevier]

Abstract: Rare disorders leading to intellectual disability, such as Fragile X syndrome (FXS) alter synaptic plasticity. Ligand identification of orphan nuclear receptors has led to the discovery of many signaling pathways and has revealed a direct link of nuclear receptors with human conditions such as mental retardation and neurodegenerative diseases. PPARγ agonists can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth. Therefore, selective PPARγ agonists are good candidates for therapeutic evaluation in intellectual disabilities. Preliminary results suggest that PPARγ agonists such as Pioglitazone, Rosiglitazone and synthetic agonist, GW1929, are used as the therapeutic agent in neurological disorders. These components interact with intracellular transduction signals (e.g. GSK3β, PI3K/Akt, Wnt/β-Catenin, Rac1 and MMP-9). It seems that interaction with these pathways can improve memory recognition in FXS animal models. The present hypothesis consists of enhancing synaptic plasticity that may then rescue the learning and memory in FXS. This will open many new therapeutic avenues for a variety of human diseases. [Copyright &y& Elsevier]

In the cerebellum, long-term depression (LTD) plays a key function in sculpting neuronal circuits to store information, since motor learning and memory are thought to be associated with such long-term changes in synaptic efficacy. To better understand the principles of transmission of information in the cerebellum, we, in our model, distinguished different types of neurons (type 1- and type 2-like) to examine the neuronal excitability and analyze the interspike interval (ISI) bifurcation phenomenon in these units, and then built a Purkinje cell circuit to study the impact of external stimulation on LTD in this circuit. According to the results of computational analysis, both climbing fiber-Purkinje cell and granule cell-Purkinje cell circuits were found to manifest LTD; the external stimuli would influence LTD by changing both depression time and depression intensity. All of the simulated results showed that LTD is a very significant factor in the Purkinje circuit networks. Finally, to deliver the learning regularities, we simulated spike timing-dependent plasticity (STDP) by increasing the CaP conductance. [ABSTRACT FROM AUTHOR]

Highlights: [•] Allantoin enhanced cognitive function in the passive avoidance task. [•] Allantoin activated the phosphorylation of PI3K-Akt-GSK-3β pathway. [•] Allantoin increased neurogenesis in the hippocampal dentate gyrus region. [Copyright &y& Elsevier]

Highlights: [•] We investigated chordin expression in the adult rat CNS using immunohistochemistry. [•] Chordin is expressed throughout the adult CNS. [•] We observed that chordin is abundantly expressed in many kinds of axons. [•] We found strong chordin expression in the apical dendrites of pyramidal cells. [•] We also exhibited chordin expression in astrocytes and ependymal cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Long-term potentiation was measured in hippocampal slices from two mouse strains. [•] The level of long-term potentiation is different in one strain than the other. [•] Social isolation stress reduces long-term potentiation expression in both strains. [•] Corticosterone levels increase after social stress isolation. [•] Long-term potentiation was restored by glucocorticoid receptor antagonist. [ABSTRACT FROM AUTHOR]

Highlights: [•] Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are involved in multiple physiological processes. [•] HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. [•] Dysregulation of HCN channels is involved in a variety of neurological disorders. [ABSTRACT FROM AUTHOR]

Abstract: Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others. GSK3 inhibitors also improve cognition following impairments caused by therapeutic interventions, such as cranial irradiation for brain tumors. These findings demonstrate that GSK3 inhibitors are able to ameliorate cognitive impairments caused by a diverse array of diseases, injury, and treatments. The improvements in impaired cognition instilled by administration of GSK3 inhibitors appear to involve a variety of different mechanisms, such as supporting long-term potentiation and diminishing long-term depression, promotion of neurogenesis, reduction of inflammation, and increasing a number of neuroprotective mechanisms. The potential for GSK3 inhibitors to repair cognitive deficits associated with many conditions warrants further investigation of their potential for therapeutic interventions, particularly considering the current dearth of treatments available to reduce loss of cognitive functions. [Copyright &y& Elsevier]

Highlights: [•] An inhibitor of kynurenine-3-monoxygenase was administered to pregnant female rats. [•] Adult offspring at postnatal day 60 (P60) showed alterations in synaptic plasticity. [•] Expression of GluN2A, sonic hedgehog and other developmental proteins was changed. [•] Most earlier protein changes had disappeared with no changes in RNA or learning tasks. [•] Prenatal kynurenine pathway inhibition produces persistent synaptic and protein changes. [Copyright &y& Elsevier]

Highlights: [•] Aβ-enhanced hippocampal LTD depends on mGluR1/5 but not NMDAR. [•] Aβ-enhanced hippocampal LTD requires the activation of p38MAPK, PTPs and capase-3. [•] Activation of STEP is involved in Aβ-enhanced hippocampal LTD. [•] Activation of TACE and mTOR is not necessary for Aβ-enhanced hippocampal LTD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Noradrenaline causes a reduction in gamma frequency oscillations in the hippocampus in vitro. [•] Noradrenaline causes a reduction in IPSPs and EPSPs during gamma frequency activity. [•] Activation of alpha-adrenergic 1 receptors reduces gamma frequency activity. [•] Activation of beta-adrenergic 1 receptors increases gamma frequency activity. [•] Noradrenaline can bidirectionally modulate network gamma oscillations via activation of different receptor subtypes. [ABSTRACT FROM AUTHOR]

Highlights: [•] The enzymatic degradation of ECM stimulates developmental forms of plasticity. [•] Weakening ECM aids functional recovery in regeneration, stroke, and amblyopia. [•] ECM molecules shape epileptogenesis and might be new valuable therapeutic targets. [•] Heparan sulfate proteoglycans regulate turnover of beta-amyloid. [ABSTRACT FROM AUTHOR]

Abstract: The cyclic nucleotides cAMP and cGMP are common signalling molecules synthesized in neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal neurons. This review will summarize the literature on cyclic nucleotide signalling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of striatal medium-sized spiny output neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of striatal MSNs as it relates to the treatment of neurological disorders such as Huntington's and Parkinson's disease. [Copyright &y& Elsevier]

Highlights: [•] Stress and models of depression preferentially decrease neurogenesis in the ventral hippocampus. [•] No consensus on regional-specificity of monoaminergic treatments. [•] Dorsal and ventral-specific actions on neurogenesis can both be associated with recovery. [•] Antidepressants do more than counteracting stress-related changes. [•] Effects on new hippocampal neurons depend upon their maturation stage. [Copyright &y& Elsevier]

Abstract: Outside of Fragile X syndrome (FXS), the role of Fragile-X Mental Retardation Protein (FMRP) in mediating neuropsychological abnormalities is not clear. FMRP, p70-S6 kinase (S6K) and protein phosphatase 2A (PP2A) are thought to cooperate as a dynamic signaling complex. In our prior work, adult rats have enhanced CA1 hippocampal long-term depression (LTD) following an early life seizure (ELS). We now show that mGluR-mediated LTD (mLTD) is specifically enhanced following ELS, similar to FMRP knock-outs. Total FMRP expression is unchanged but S6K is hyperphosphorylated, consistent with S6K overactivation. We postulated that either disruption of the FMRP–S6K–PP2A complex and/or removal of this complex from synapses could explain our findings. Using subcellular fractionation, we were surprised to find that concentrations of FMRP and PP2A were undisturbed in the synaptosomal compartment but reduced in parallel in the cytosolic compartment. Following ELS FMRP phosphorylation was reduced in the cytosolic compartment and increased in the synaptic compartment, in parallel with the compartmentalization of S6K activation. Furthermore, FMRP and PP2A remain bound following ELS. In contrast, the interaction of S6K with FMRP is reduced by ELS. Blockade of PP2A results in enhanced mLTD; this is occluded by ELS. This suggests a critical role for the location and function of the FMRP–S6K–PP2A signaling complex in limiting the amount of mLTD. Specifically, non-synaptic targeting and the function of the complex may influence the “set-point” for regulating mLTD. Consistent with this, striatal-enriched protein tyrosine phosphatase (STEP), an FMRP “target” which regulates mLTD expression, is specifically increased in the synaptosomal compartment following ELS. Further, we provide behavioral data to suggest that FMRP complex dysfunction may underlie altered socialization, a symptom associated and observed in other rodent models of autism, including FXS. [Copyright &y& Elsevier]

Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant monogenetic disorder that is characterized by the formation of benign tumors in several organs as well as brain malformations and neuronal defects. TSC is caused by inactivating mutations in one of two genes, TSC1 and TSC2, resulting in increased activity of the mammalian Target of Rapamycin (mTOR). Here, we explore the cytoarchitectural and functional CNS aberrations that may account for the neurological presentations of TSC, notably seizures, hydrocephalus, and cognitive and psychological impairments. In particular, recent mouse models of brain lesions are presented with an emphasis on using electroporation to allow the generation of discrete lesions resulting from loss of heterozygosity during perinatal development. Cortical lesions are thought to contribute to epileptogenesis and worsening of cognitive defects. However, it has recently been suggested that being born with a mutant allele without loss of heterozygosity and associated cortical lesions is sufficient to generate cognitive and neuropsychiatric problems. We will thus discuss the function of mTOR hyperactivity on neuronal circuit formation and the potential consequences of being born heterozygous on neuronal function and the biochemistry of synaptic plasticity, the cellular substrate of learning and memory. Ultimately, a major goal of TSC research is to identify the cellular and molecular mechanisms downstream of mTOR underlying the neurological manifestations observed in TSC patients and identify novel therapeutic targets to prevent the formation of brain lesions and restore neuronal function. [Copyright &y& Elsevier]

Highlights: [•] We investigated the role of thalamic activation in rat auditory cortical plasticity. [•] Focal electrical stimulation of thalamic neurons evoked field potential shifts. [•] Thalamic activation induced potentiation or depression of local field potentials. [•] These changes rely upon the activation of different frequency-specific TC pathways. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder. [Copyright &y& Elsevier]

Abstract: Abnormalities in dendritic spines have commonly been observed in brain specimens from epilepsy patients and animal models of epilepsy. However, the functional implications and clinical consequences of this dendritic pathology for epilepsy are uncertain. Dendritic spine abnormalities may promote hyperexcitable circuits and seizures in some types of epilepsy, especially in specific genetic syndromes with documented dendritic pathology, but in these cases it is difficult to differentiate their effects on seizures versus other comorbidities, such as cognitive deficits and autism. In other situations, seizures themselves may cause damage to dendrites and dendritic spines and this seizure-induced brain injury may then contribute to progressive epileptogenesis, memory problems and other neurological deficits in epilepsy patients. The mechanistic basis of dendritic spine abnormalities in epilepsy has begun to be elucidated and suggests novel therapeutic strategies for treating epilepsy and its complications. [Copyright &y& Elsevier]

Abstract: Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by a progressive loss of cognition and the presence of two hallmark lesions, senile plaques (SP) and neurofibrillary tangles (NFT), which result from the accumulation and deposition of the β-amyloid peptide (Aβ) and the aggregation of hyperphosphorylated tau protein, respectively. Initially, it was thought that Aβ fibrils, which make up SP, were the root cause of the massive neurodegeneration usual found in AD brains. Over time, the longstanding emphasis on fibrillar Aβ deposits and neuronal death slowly gave way to a new paradigm involving soluble oligomeric forms of Aβ, which play a prominent role in triggering the cognitive deficits by specifically targeting synapses and disrupting synaptic signaling pathways. While this paradigm is widely accepted today in the AD field, the molecular details have not been fully elucidated. In this review, we address some of the important evidence, which has led to the Aβ oligomer-centric hypothesis as well as some of the key findings concerning the effects of Aβ oligomers on synapses at a morphological and functional level. Understanding how Aβ oligomers target synapses provides an important framework for ongoing AD research, which can lead to the development of successful therapeutic strategies designed to alter or perhaps reverse the course of the disease. [Copyright &y& Elsevier]