Neuropeptide Y (NPY): functions and biosynthesis as a peptidergic neurotransmitter and the regulation of neuron-specific expression of NPY gene

Neuropeptide Y (NPY) is widely distributed in the central and sympathetic nervous systems and has a variety of central actions including regulation of blood pressure and peripheral actions; e.g., continuous vasoconstriction and inhibition of catecholamine release. The NPY receptor can be divided into 2 subclasses (Y1, Y2), and these subclasses are coupled to GTP binding proteins (Gi, Go, Gp ......). Recently, human and rat prepro-NPY mRNA and NPY gene structures have been determined by cDNA and genomic cloning and sequencing. The strong evolutionary conservation of these structures suggested that NPY is an essential peptidergic neurotransmitter. Little is known about the biosynthesis, processing, degradation of NPY and NPY gene expression. We showed that NPY gene expression and NPY biosynthesis are regulated by neural activity, hormone, and intracellular second messengers via neurotransmitter receptors. The change of NPY gene expression by these neural factors is considered to be a good model for a synaptic plasticity, because these changes cause the changes of synaptic transmission. Furthermore, because NPY is expressed in sympathetic neurons and its gene expression increased markedly on the differentiation of adrenergic cells, this study about NPY gene expression could provide good clues for elucidating the differentiation of sympathetic neurons.     

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Adaptive plasticity of NMDA receptors and dendritic spines: implications for enhanced vulnerability of the adolescent brain to alcohol addiction

It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears to be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, "fix" the addictive behavior in the adolescent and young adult brain.     

Environmental influences on brain neurotrophins in rats

Environmental factors can have profound influences on the brain. Enriching environments with physical, social and sensory stimuli are now established to be beneficial to brain development and ageing. A multitude of responses from cellular and molecular mechanisms to macroscopic changes in neural morphology and neurogenesis have been considered in the context for evidences that environmental inputs can regulate brain plasticity in the rat at all stages of life. Data from our laboratory have revealed that enriched environment increased nerve growth factor (NGF) gene expression and protein levels in the hippocampus, and this may contribute to events underlying environmentally induced neural plasticity. Because neurotrophic factors are essential for neural development and survival, they are likely to be involved in the cerebral consequences modified by enriched experiences.     

The immediate early gene Arc is associated with behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder.

Mechanisms involved in adaptative and maladaptive changes in neural plasticity and synaptic efficacy in various brain areas are pivotal to understanding the physiology of the response to stress and the pathophysiology of posttraumatic stress disorder (PTSD). Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene (IEG) which has direct effects on intracellular homeostatic functions. Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory. It may thus play an important role in mediating experience-induced reorganization and/or development of synaptic connections. This study sought to characterize the pattern of expression of mRNA for the Arc gene in selected brain areas of test subjects classified according to their individual pattern of behavioral response to a stressor, correlated with circulating levels of corticosterone (as a physiological marker of stress response). The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc, compared to unexposed controls. The group whose behavior was severely disrupted demonstrated no such upregulation. Consistent with the hypothesis that the Arc gene has a promoting effect on neuronal function and/or structural changes, the lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure.     

Neuronal Ca2+/calmodulin-dependent protein kinase II--discovery, progress in a quarter of a century, and perspective: implication for learning and memory

Much has been learned about the activity-dependent synaptic modifications that are thought to underlie memory storage, but the mechanism by which these modifications are stored remains unclear. A good candidate for the storage mechanism is Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). CaM kinase II is one of the most prominent protein kinases, present in essentially every tissue but most concentrated in brain. Although it has been about a quarter of a century since the finding, CaM kinase II has been of the major interest in the region of brain science. It plays a multifunctional role in many intracellular events, and the expression of the enzyme is carefully regulated in brain regions and during brain development. Neuronal CaM kinase II regulates important neuronal functions, including neurotransmitter synthesis, neurotransmitter release, modulation of ion channel activity, cellular transport, cell morphology and neurite extension, synaptic plasticity, learning and memory, and gene expression. Studies concerning this kinase have provided insight into the molecular basis of nerve functions, especially learning and memory, and indicate one direction for studies in the field of neuroscience. This review presents the molecular structure, properties and functions of CaM kinase II, as a major component of neurons, based mainly developed on findings made in our laboratory.     

Molecular mechanism of learning and memory based on the research for Ca2+/calmodulin-dependent protein kinase II

In the central nervous system (CNS), the synapse is a specialized junctional complex by which axons and dendrites emerging from different neuron intercommunicates. Changes in the efficiency of synaptic transmission are important for a number of aspects of neural function. Much has been learned about the activity-dependent synaptic modifications that are thought to underlie memory storage, but the mechanism by which these modifications are stored remains unclear. Thus, it is important to find and characterize "memory molecules," and "memory apparatus or memory forming apparatus." A good candidate for the storage mechanism is Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II). CaM kinase II is one of the most prominent protein kinases, present in essentially every tissue but most concentrated in the brain. Neuronal CaM kinase II regulates important neuronal functions, including neurotransmitter synthesis, neurotransmitter release, modulation of ion channel activity, cellular transport, cell morphology and neurite extension, synaptic plasticity, learning and memory, and gene expression. Studies concerning this kinase open a door of the molecular basis of nerve function, especially learning and memory, and indicate one direction for the studies in the field of neuroscience. This review presents molecular structure, properties and functions of CaM kinase II, as a major component of neuron, which are mainly developed in our laboratory.     

Brain-derived neurotrophic factor and antidepressant activity

Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning. There are several lines of evidence supporting a role for BDNF in the treatment of depression. This paper reviews the neurotrophin hypothesis of antidepressant action, and examines our current understanding of activity-dependent mechanisms of BDNF expression and function in limbic regions of the brain. Our discussion starts with the original observations of monoaminergic neurotransmitter dysfunction that served as the basis for early antidepressant drug development, and outlines evidence for neurodegeneration and functional deficits existing with chronic stress and depression. We continue with evidence that enhancement in neurotrophic support and associated augmentation in synaptic plasticity and function may form the basis for antidepressant efficacy, and serve as a current and future focus in the quest for more rapid-acting and effective medication treatments. Finally, we follow the current search for the intracellular mechanisms of antidepressant interventions that may bring the monoaminergic and neurotrophic hypotheses together, and help us to more fully understand the roles of both neurotransmitter and growth factor. Principal challenges to the neurotrophin hypothesis, and inconsistencies between clinical and preclinical research results, are also pointed out, as these also guide future experiments that will refine our understanding of treatment mechanisms.     

Neuroinflammation and synaptic plasticity: theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders

The fascinating capacity that the central nervous system (CNS) has for encoding and retaining memories is thought to be based on activity-dependent forms of synaptic plasticity. The CNS and the immune systems are known to be engaged in an intense bidirectional crosstalk, and glial cells are now viewed as a crucial third element of the synapse. In this opinion article, we review the principal mechanisms by which the immune system, and in particular immune diffusible mediators, influences synaptic transmission and the induction of brain plastic phenomena. Thereafter, we consider the potential implications of inflammation-related overexpression of diffusible mediators in the disruption of synaptic plastic processes and neuronal networks functioning during human neurological diseases. Finally, we propose that a more accurate characterization of the mechanisms underlying the immune-mediated control of synaptic plasticity could represent, in the future, the basis for the development of a novel immune-centred therapeutic approach to neurological disorders.     

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.     

Neural network dysfunction in Alzheimer's disease: a drug development perspective

Over the last few years, a major focus of Alzheimer's disease research has been to understand the mechanisms by which build-up of the beta-amyloid protein (Abeta) in the brain leads to chronic neurodegeneration and eventual cell death. It is increasingly recognized that cell death is not a major cause of dementia. Indeed, recent studies suggest that Abeta causes neuritic dystrophy and interferes with mechanisms of synaptic plasticity such as long-term potentiation. There are also a number of well-described homeostatic mechanisms in the brain that help to maintain signal strength as a consequence of lowered synaptic input, which may occur as a consequence of neuritic dystrophy. This review examines mechanisms of synaptic scaling in the brain and explores prospects for future drug development based on a neural network perspective.     

DEVELOPMENT OF PERIPHERAL AUTONOMIC SYNAPSES: NEUROTRANSMITTER RECEPTORS, NEUROEFFECTOR ASSOCIATIONS AND NEURAL INFLUENCES

1. The functional innervation of autonomic target tissues occurs early during development, at a time when both the nerves and post-synaptic target tissues are still differentiating. 2. Physiological responses appear soon after the arrival of the first fibres when uptake and release mechanisms within the nerves are already functional. Initial responses differ from those in the mature animal, both in the form and, frequently, in the subtypes of receptors involved. 3. Results of a number of studies suggest that the initial expression of neurotransmitter receptors during development is largely independent of neural influences. Changes recorded in neurotransmitter receptor expression during development appear to be similarly independent of neural influences. 4. While signal transduction pathways coupling adrenergic neurotransmitter receptors to effector responses appear to develop independently of the nerves, the efficient coupling of muscarinic receptors often requires the action of the neurotransmitter, acetylcholine. 5. During the period of synapse formation, the neural plexus continues to expand. While developing varicosities can release the neurotransmitter, the capacity for neurotransmitter retention appears to be restricted. Developmental changes in the neurotransmitters that produce functional responses, while well known in the sweat glands, may also be seen in more subtle forms in other target tissues. 6. Ultrastructural studies suggest that close physical associations between the membranes of the release sites of the developing nerves and the target cells may form early during development when physiological responses are still immature. These close associations could enable more specific reciprocal interactions between nerves and target cells involving known and novel growth factors, neuropeptides and cytokines important in shaping the mature synaptic characteristics.     

Opiates and plasticity

Opiates are among the most powerful analgesics and pain-relieving agents. However, they are potentially extremely addictive thereby limiting their medical use, making them exceedingly susceptible to abuse and adding to the global drug problem. It is believed that positive memories associated with the pleasurable effects of opiates and negative memories associated with dysphoria during opiate withdrawal contribute to compulsive opiate-seeking behavior characterizing addiction. There is a vast amount of available data regarding the neuroadaptations in response to opiates during opiate tolerance, dependence and withdrawal that contribute to opiate addiction, yet it is still a major challenge to identify the neurobiological adaptations that underlie the hallmarks of opiate addiction such as compulsive drug use, and relapse to drug seeking. Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning and addiction have been recognized. Consequently, the current notion of addiction supports the idea that aberrant forms of drug-induced synaptic plasticity and learning in the brain drive addictive behaviors. Here we discuss current progress on some of the recently identified forms of synaptic plasticity at excitatory and inhibitory synapses in opioid-sensitive areas of the brain that are targeted by opiates and other addictive drugs. The neuroadaptations involved in opiate tolerance, dependence and withdrawal will be re-visited since they share many features with synaptic learning mechanisms.This article is part of a Special Issue entitled ‘Synaptic Plasticity and Addiction’.     

Study on the regulation of synaptic function by Ca2+/calmodulin-dependent protein kinase II

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is one of the most abundant protein kinases in the mammalian brain, especially in the hippocampus. Neuronal CaMKII is a multifunctional mediator of activity dependent on an increase in the Ca(2+) level in excitable cells. It plays an important role in synaptic plasticity, including learning and memory, and is recognized as a "memory molecule." The expression of the kinase increases most rapidly during the most active phase in the formation of synapses in the postnatal brain and remains at a high level after synaptic maturation, indicating that the kinase is carefully regulated in the space-temporal gene expression. It is accumulated in the postsynaptic density (PSD), which is central in synaptic transmission. This review presents the gene expression and alternative splicing of CaMKII during neural differentiation, molecular constituents of PSD, and regulation of CaMKII by activity-regulated cytoskeleton-associated protein (Arc) mainly developed in our study.     

Interrogating the function of GABAA receptors in the brain with optogenetic pharmacology

To better understand neural circuits and behavior, microbial opsins have been developed as optogenetic tools for stimulating or inhibiting action potentials with high temporal and spatial precision. However, if we seek a more reductionist understanding of how neuronal circuits operate, we also need high-resolution tools for perturbing the function of synapses. By combining photochemical tools and molecular biology, a wide variety of light-regulated neurotransmitter receptors have been developed, enabling photo-control of excitatory, inhibitory, and modulatory synaptic transmission. Here we focus on photo-control of GABA_A receptors, ligand-gated Cl⁻ channels that underlie almost all synaptic inhibition in the mammalian brain. By conjugating a photoswitchable tethered ligand onto a genetically-modified subunit of the GABA_A receptor, light-sensitivity can be conferred onto specific isoforms of the receptor. Through gene editing, this attachment site can be knocked into the genome, enabling photocontrol of endogenous GABA_A receptors. This strategy can be employed to explore the cell biology and neurophysiology of GABA_A receptors. This includes investigating how specific isoforms contribute to synaptic and tonic inhibition and understanding the roles they play in brain development, long-term synaptic plasticity, and learning and memory.     

胶质细胞介导的神经突触修剪在阿尔茨海默病中的作用

阿尔茨海默病(Alzheimer's disease,AD)是一种以记忆丧失、认知障碍为主要特征的神经退行性疾病,迄今尚无有效的治疗策略.神经突触是大脑神经元之间联系的部位,是产生记忆及其他神经活动的关键组成部分,神经突触的丢失是AD的重要病理特征.胶质细胞是大脑中除神经元以外的一类至关重要的细胞,其中最主要的两类胶质...     

Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs.     

Chronic antidepressant treatment induces contrasting patterns of synaptophysin and PSA-NCAM expression in different regions of the adult rat telencephalon.

Structural modifications occur in the brain of severely depressed patients and they can be reversed by antidepressant treatment. Some of these changes do not occur in the same direction in different regions, such as the medial prefrontal cortex, the hippocampus or the amygdala. Differential structural plasticity also occurs in animal models of depression and it is also prevented by antidepressants. In order to know whether chronic fluoxetine treatment induces differential neuronal structural plasticity in rats, we have analyzed the expression of synaptophysin, a protein considered a marker of synaptic density, and the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule involved in neurite and synaptic remodeling. Chronic fluoxetine treatment increases synaptophysin and PSA-NCAM expression in the medial prefrontal cortex and decreases them in the amygdala. The expression of these molecules is also affected in the entorhinal, the visual and the somatosensory cortices.     

国家“重大新药创制”科技重大专项重点关注靶点分析解读——AMPA受体

AMPA受体是兴奋性神经递质谷氨酸的非N-甲基-D-天冬氨酸型离子型跨膜受体,其介导中枢神经系统快速兴奋性突触传递,在中枢神经系统的信号传导、神经发育以及突触的可塑性等方面有重要的影响。研究表明,多种疾病如神经精神系统疾病、心血管疾病、肿瘤、呼吸系统疾病、内分泌系统疾病的发生发展与AMPA受体数量或功能的异常密切相关。近年来,AMPA受体作为一种理想的药物作用靶点,受到了越来越多的关注。结合汤森路透数据库资源——ThomsonReutersIntegrity和CortellisforCompetitiveIntelligence,对AMPA受体的机制、相关药物研究进展、适应证、研发机构、交易、专利、文献等情报进行数据层面的分析。