Function and Regulation of Postsynaptic Serine Racemase

突触后丝氨酸消旋酶的功能和调控

基本信息

  • 批准号:
    10357566
  • 负责人:
  • 金额:
    $ 47.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-05 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic and genetic data implicates a dysregulation of N-methyl-D-aspartate receptor (NMDAR) function. NMDARs are ligand-gated ion channels that play critical roles in neurodevelopment and synaptic plasticity and subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. Thus, there is a critical need for a detailed understanding of the molecular mechanisms involved in the regulation of NMDARs which will yield insights into the pathophysiology of schizophrenia and facilitate the development of novel therapeutic strategies. Unlike all other neurotransmitter receptors, NMDARs have an absolute requirement for the binding of two different agonists in order to be activated. In addition to glutamate released from the presynaptic terminal, NMDARs require a co-agonist, which can be either glycine or D-serine. At most forebrain synapses, D-serine is the primary NMDAR co-agonist and D-serine deficiency has been implicated in the pathophysiology of schizophrenia. However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains quite limited. Even the cellular source of D-serine is fiercely debated. D-serine is synthesized in the brain by the enzyme serine racemase (SR) that converts L-serine to D-serine. Original studies placed both SR and D-serine in astrocytes, and activity-dependent release of D-serine from astrocytes was venerated as the prototypical gliotransmitter. However, a growing literature using more selective antibodies and mouse genetics has challenged this astrocytic role in D-serine regulation and pointed to a primarily neuronal source. In this proposal, conditional SR knock-out mice were injected with viral constructs into the hippocampus to remove SR in only a few individual neurons. By comparing the effects of SR deletion to adjacent control neurons, we have obtained preliminary data that provides the first rigorously- controlled evidence for a functional role of neuronal D-serine. This preliminary data supports our central hypothesis that synaptic NMDAR activity and function is regulated by postsynaptic SR and D-serine release. In Specific Aim 1, the cell-autonomous effects of postsynaptic SR deletion will be characterized and the source of the remaining synaptic co-agonist will be determined. In Specific Aim 2, we will examine in detail the effects of postsynaptic SR deletion on both postsynaptic and presynaptic NMDARs. In Specific Aim 3, we will determine the functional role of postsynaptic SR, using an innovative molecular replacement approach to replace endogenous SR with characterized recombinant SR mutants to explore the function and regulation of postsynaptic SR. Successful completion of this research program will provide a better understanding of the molecular mechanisms regulating co-agonist availability at synaptic NMDARs, and how these processes might be disrupted in disease states, helping to lead towards our long-term goal of developing novel disease-modifying approaches to treat schizophrenia and other complex neuropsychiatric disorders.
尽管精神分裂症的病因机制在很大程度上仍不清楚,但药理学和遗传数据的融合表明 N-甲基-D-天冬氨酸受体 (NMDAR) 功能失调。 NMDAR 是配体门控离子通道,在神经发育和突触可塑性中发挥着关键作用,NMDAR 功能的细微变化可能会产生广泛的发育和认知影响。因此,迫切需要详细了解 NMDAR 调节所涉及的分子机制,这将深入了解精神分裂症的病理生理学并促进新治疗策略的开发。与所有其他神经递质受体不同,NMDAR 绝对需要结合两种不同的激动剂才能被激活。除了从突触前末端释放的谷氨酸之外,NMDAR 还需要一种共激动剂,可以是甘氨酸或 D-丝氨酸。在大多数前脑突触中,D-丝氨酸是主要的 NMDAR 共激动剂,D-丝氨酸缺乏与精神分裂症的病理生理学有关。然而,我们对调节突触 D-丝氨酸可用性的机制的理解仍然相当有限。甚至 D-丝氨酸的细胞来源也存在激烈争论。 D-丝氨酸在大脑中由丝氨酸消旋酶 (SR) 合成,该酶将 L-丝氨酸转化为 D-丝氨酸。最初的研究将 SR 和 D-丝氨酸置于星形胶质细胞中,并且星形胶质细胞中 D-丝氨酸的活性依赖性释放被尊崇为典型的神经胶质递质。然而,越来越多的文献使用更具选择性的抗体和小鼠遗传学,对星形胶质细胞在 D-丝氨酸调节中的作用提出了挑战,并指出了主要的神经元来源。在该提议中,条件性 SR 敲除小鼠的海马体内注射了病毒构建体,仅去除少数单个神经元中的 SR。通过比较 SR 缺失对邻近对照神经元的影响,我们获得了初步数据,为神经元 D-丝氨酸的功能作用提供了第一个严格控制的证据。该初步数据支持我们的中心假设,即突触 NMDAR 活性和功能受突触后 SR 和 D-丝氨酸释放调节。在具体目标 1 中,将表征突触后 SR 缺失的细胞自主效应,并确定剩余突触共激动剂的来源。在具体目标 2 中,我们将详细研究突触后 SR 缺失对突触后和突触前 NMDAR 的影响。在具体目标3中,我们将确定突触后SR的功能作用,采用创新的分子替代方法,用特征性的重组SR突变体替代内源性SR,以探索突触后SR的功能和调控。该研究项目的成功完成将有助于更好地了解调节突触 NMDAR 共激动剂可用性的分子机制,以及这些过程在疾病状态下如何被破坏,有助于实现我们开发新的疾病缓解方法来治疗精神分裂症和其他复杂神经精神疾病的长期目标。

项目成果

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John Alan Gray其他文献

John Alan Gray的其他文献

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{{ truncateString('John Alan Gray', 18)}}的其他基金

Function and Regulation of Postsynaptic Serine Racemase
突触后丝氨酸消旋酶的功能和调控
  • 批准号:
    10091320
  • 财政年份:
    2019
  • 资助金额:
    $ 47.5万
  • 项目类别:
Function and Regulation of Postsynaptic Serine Racemase
突触后丝氨酸消旋酶的功能和调控
  • 批准号:
    10570850
  • 财政年份:
    2019
  • 资助金额:
    $ 47.5万
  • 项目类别:
Function and Regulation of Postsynaptic Serine Racemase
突触后丝氨酸消旋酶的功能和调控
  • 批准号:
    9908174
  • 财政年份:
    2019
  • 资助金额:
    $ 47.5万
  • 项目类别:
Synaptic targeting and regulation of NMDAR subunits
NMDAR 亚基的突触靶向和调节
  • 批准号:
    8488206
  • 财政年份:
    2013
  • 资助金额:
    $ 47.5万
  • 项目类别:
Synaptic targeting and regulation of NMDAR subunits
NMDAR 亚基的突触靶向和调节
  • 批准号:
    9039662
  • 财政年份:
    2013
  • 资助金额:
    $ 47.5万
  • 项目类别:
Synaptic targeting and regulation of NMDAR subunits
NMDAR 亚基的突触靶向和调节
  • 批准号:
    8647007
  • 财政年份:
    2013
  • 资助金额:
    $ 47.5万
  • 项目类别:
Synaptic targeting and regulation of NMDAR subunits
NMDAR 亚基的突触靶向和调节
  • 批准号:
    8775587
  • 财政年份:
    2013
  • 资助金额:
    $ 47.5万
  • 项目类别:

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