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Abstract Objective d-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc). Methods d-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. Results d-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD). Conclusion d-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc.

Objective: d-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc). Methods: d-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. Results: d-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD). Conclusion: d-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc. [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: [•] 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]

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: 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]

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]

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: Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity-related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents. [Copyright &y& Elsevier]

Abstract: Huntington’s disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease. [Copyright &y& Elsevier]

Highlights: [•] The effects of stress on neuronal plasticity largely differ between brain regions. [•] Brain adaptation to stress involves coordinated and region-specific changes in gene expression. [•] microRNAs are small non-coding RNAs involved in fine regulation of gene expression. [•] In brain regions affected by stress, microRNAs are important regulators of neuronal plasticity. [•] Here, we focus on molecular mechanisms imparting specificity to target regulation by microRNAs. [ABSTRACT FROM AUTHOR]

Neural inhibition in the brain is mainly mediated by ionotropic γ-aminobutyric acid type A (GABAA) receptors. Different subtypes of these receptors, distinguished by their subunit composition, are either concentrated at postsynaptic sites where they mediate phasic inhibition or found at perisynaptic and extrasynaptic locations where they prolong phasic inhibition and mediate tonic inhibition, respectively. Of special interest are mechanisms that modulate the stability and function of postsynaptic GABAA receptor subtypes and that are implicated in functional plasticity of inhibitory transmission in the brain. We will summarize recent progress on the classification of synaptic versus extrasynaptic receptors, the molecular composition of the postsynaptic cytoskeleton, the function of receptor-associated proteins in trafficking of GABAA receptors to and from synapses, and their role in post-translational signaling mechanisms that modulate the stability, density, and function of GABAA receptors in the postsynaptic membrane. [Copyright &y& Elsevier]

The brain renin–angiotensin system (RAS) has long been known to regulate several classic physiologies including blood pressure, sodium and water balance, cyclicity of reproductive hormones and sexual behaviors, and pituitary gland hormones. These physiologies are thought to be under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AT2 receptor subtype is expressed during fetal development and is less abundant in the adult. This receptor appears to oppose growth responses facilitated by the AT1 receptor, as well as growth factor receptors. Recent evidence points to an important contribution by the brain RAS to non-classic physiologies mediated by the newly discovered angiotensin IV (AngIV)/AT4 receptor subtype system. These physiologies include the regulation of blood flow, modulation of exploratory behavior, and a facilitory role in learning and memory acquisition. This system appears to interact with brain matrix metalloproteinases in order to modify extracellular matrix molecules thus permitting the synaptic remodeling critical to the neural plasticity presumed to underlie memory consolidation, reconsolidation, and retrieval. There is support for an inhibitory influence by AngII activation of the AT1 subtype, and a facilitory role by AngIV activation of the AT4 subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning. The discovery of the AT4 receptor subtype, and its facilitory influence upon learning and memory, suggest an important role for the brain RAS in normal cognitive processing and perhaps in the treatment of dysfunctional memory disease states. [Copyright &y& Elsevier]

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA’s actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches. [Copyright &y& Elsevier]

We investigated the relationship between Arc (activity-regulated cytoskeleton-associated protein) and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Arc and CaM kinase II were concentrated in the postsynaptic density. These proteins were accumulated after electroconvulsive treatment. Arc increased about 2.5-fold within 30 min and was maintained at this level for 8 h after the stimulation. CaM kinase II also increased within 30 min and remained at this level for at least 24 h. The interaction of Arc with CaM kinase II was demonstrated using GST-Arc fusion protein, and confirmed in neuroblastoma cells by immunoprecipitation. We examined the function of Arc by introducing Arc cDNA into neuroblastoma cells expressing CaM kinase II. The cells expressing both Arc and CaM kinase II had longer neurites than those expressing CaM kinase II alone. Arc itself did not promote neurite outgrowth. The growth of neurites by Arc was completely blocked by treatment with KN62, an inhibitor of CaM kinases. These results indicated that Arc potentiated the action of CaM kinase II for neurite extension. [Copyright &y& Elsevier]

Brain plasticity refers to the ability of the brain to undergo structural and functional changes. It is a necessary process that allows us to adapt and learn from our environment and is fundamental to our survival. However, under certain conditions, these neuroadaptive responses can have adverse consequences. In particular, increasing evidence indicates that plastic processes are coopted by drugs of abuse, leading to addiction and associated drug-seeking behaviors. An extensive and diverse group of studies ranging from the molecular to the behavioral level has also strongly implicated glutamatergic neurotransmission as a critical mediator of experience-dependent synaptic plasticity. Thus, it is vital to understand how drugs of abuse interact and potentially alter glutamatergic neurotransmission and associated signal transduction processes. This review will focus on the cellular and molecular neuroscience of alcoholism, with emphasis on events at the glutamatergic postsynaptic density (PSD) and dendritic spine dynamics that appear to underlie much of the structural and functional plasticity of the CNS. [Copyright &y& Elsevier]

Neuronal responses to electrical activity-induced calcium signals are specified by the localization of the calcium entry site and the spatial properties of the calcium transient. Calcium flux through NMDA receptors located in the synapse initiates changes in synaptic efficacy and promotes pro-survival events, whereas calcium flux through extrasynaptic NMDA receptors is coupled to cell death pathways. The dialogue between the synaptic NMDA receptors and the nucleus is also modulated by extrasynaptic NMDA receptors, which shut down activity of CRE-binding protein (CREB) and antagonize the increase in brain-derived neurotrophic factor (BDNF) expression induced by synaptic NMDA receptors. The specification of the biological response by the localization of the receptor activated is a new concept in neuronal calcium signalling that can explain many of the opposing roles of NMDA receptors. [Copyright &y& Elsevier]

Recent advances have been made in understanding the changes in neuronal plasticity in psychiatric disease at the molecular level (changes in neurotransmission, long-term potentiation, long-term depression, glutamate receptors, synaptic strength and neurotrophic support) and the systems level (changes in hippocampal, frontal and amygdala function in health and disease and the impact of stress on the hippocampal/frontal axis), as well as in the impact of drugs and sites of action for therapeutic intervention. Drugs acting on plasticity could affect the abnormal set point in psychiatric disease, resulting in treatment of the disease rather than just the symptoms. [Copyright &y& Elsevier]

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca2+ channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal–neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity. [Copyright &y& Elsevier]

Polysialic acid is a unique carbohydrate composed of a linear homopolymer of α2,8-linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) via a typical N-linked glycan in vertebrate neural system. Polysialic acid plays critical roles in neural development by modulating adhesive property of NCAM such as neural cell migration, neurite outgrowth, neural pathfinding, and synaptogenesis. The expression of polysialic acid is temporally and spatially regulated during neural development. Polysialylation of NCAM is catalyzed by two polysialyltransferases, ST8Sia II (STX) and ST8Sia IV (PST), which belong to the family of six genes encoding α2,8-sialyltransferases. ST8Sia II and IV are expressed differentially in tissue-specific and cell-specific manners, and they apparently have distinct roles in development and organogenesis. The presence of polysialic acid is always associated with expression of ST8Sia II and/or IV, suggesting that ST8Sia II and IV are the key enzymes that control the expression of polysialic acid. Both ST8Sia II and IV can transfer multiple α2,8-linked sialic acid residues to an acceptor N-glycan containing a NeuNAcα2→3 (or 6) Galβ1→4GlcNAcβ1→R structure without participation of other enzymes. The two enzymes differently but cooperatively act on NCAM and the amount of polysialic acid synthesized by both enzymes together is greater than that synthesized by either enzyme alone. The polysialyltransferases are thus important regulators in polysialic acid synthesis and contribute to neural development in the vertebrate. [Copyright &y& Elsevier]

The N-methyl-d-aspartate (NMDA) receptor is an example of a heteromeric ligand-gated ion channel that interacts with multiple intracellular proteins by way of different subunits. NMDA receptors are composed of seven known subunits (NR1, NR2A–D, NR3A–B). The present review focuses on the NR2B subunit of the receptor. Over the last several years, an increasing number of reports have demonstrated the importance of the NR2B subunit in a variety of synaptic signaling events and protein-protein interactions. The NR2B subunit has been implicated in modulating functions such as learning, memory processing, pain perception, and feeding behaviors, as well as being involved in a number of human disorders. The following review provides a summary of recent findings regarding the structural features, localization, functional properties, and regulation of the NR2B subunit. The review concludes with a section discussing the role of NR2B in human diseases. [Copyright &y& Elsevier]

Zolpidem is a rapid-onset, short-duration, quickly eliminated imidazopyridine hypnotic. It has been suggested that zolpidem may produce less memory and cognitive impairment than benzodiazepines (BZs) due to its low binding affinity for BZ receptor subtypes found in areas of the brain that are involved in learning and memory, in particular the hippocampus. A novel protocol for inducing long-term synaptic depression through activation of γ-aminobutyric acid (GABAA) receptors in the hippocampal slices has been recently reported. The authors used the CA1 region of rat hippocampal slices to compare the effects of classic BZs, which bind equipotently to BZ1 and BZ2 sites, and of nonbenzodiazepine zolpidem, which binds preferentially to the BZ1 sites of GABAA receptors, on the GABAA-induced long-term depression (LTD), a possible cellular mechanism for their different cognition-impairment profile. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that diazepam and cholordiazepoxide at concentrations of 10 and 20 μM, which did not have any effect themselves on the population spike, potentiate the ability of muscimol to induce LTD, whereas zolpidem at concentrations of 10 and 20 μM failed to potentiate muscimol-induced LTD. The results suggest that the potentiation of muscimol-induced LTD by diazepam or chlordiazepoxide and the lack of this effect by zolpidem may explain their different cognition impairment profiles. [Copyright &y& Elsevier]

γ-Aminobutyric acidA (GABAA) receptors are ligand-gated ion channels that mediate the majority of fast synaptic inhibition in the brain and that are also important drug targets for benzodiazepines, barbiturates, and neurosteriods. These receptors are pentameric hetero-oligomers that can be assembled from 7 subunit classes with multiple members: α(1–6), β(1–3), γ(1–3), δ, ϵ, θ, and π. Most receptor subtypes in the brain, however, are believed to be composed of α-, β-, and γ-subunits. Modifications of GABAA receptor function are continually implicated in a range of pathologies, including epilepsy, anxiety, insomnia, and substance abuse. Moreover, changes in the efficacy of synaptic inhibition mediated by GABAA receptors are believed to be play central roles in certain forms of synaptic plasticity, including rebound potentiation in the cerebellum, and hippocampal long-term potentiation. Given the critical role that GABAA receptors play as mediators of synaptic transmission, it is of fundamental importance to understand the endogenous mechanisms used by neurones to control the function of these receptors. This review will focus on the dynamic regulation of GABAA receptor phosphorylation state and channel function as mechanisms involved in determining the efficacy of synaptic inhibition. In addition, the possible role of GABAA receptor phosphorylation in controlling receptor internalization and recycling will also be explored. [Copyright &y& Elsevier]