权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

NMDA receptor hypofunction contributes to the dendritic dysplasia in schizophreni

NMDA 受体功能低下导致精神分裂症患者树突状发育不良

基本信息

批准号：
9264589
负责人：
DARRICK T BALU
金额：
$ 23.58万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264589
关键词：
Affect Agonist Atrophic Award Behavior Binding Biological Brain Brain Diseases Brain-Derived Neurotrophic Factor Cerebrospinal Fluid Chronic Complex Consultations Coupled Cyclic AMP Response Element Dendritic Spines Disease Dysplasia Enzymes Event Exhibits Functional disorder Genes Genetic Glutamates Glycine Goals Hippocampus (Brain)Impairment In Vitro Individual Intervention Laboratories Link Measures Mediating Mental disorders Mentors Mentorship Messenger RNA Meta-Analysis Molecular Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors Neurites Neuronal Plasticity Neurons Pathologic Pathology Pathway interactions Pattern Pharmacology Phase Population Presynaptic Terminals Production Proteins Regulation Research Rodent Schizophrenia Serine Serum Signal Transduction Site Subfamily lentivirinae Sum Symptoms Synapses Testing Therapeutic Effect Therapeutic Intervention Training Transcript Translations Vertebral column Virus chromatin immunoprecipitation cognitive function density dentate gyrus design functional outcomes granule cell in vivo mouse model mutant mouse model neurotransmission new therapeutic target novel overexpression postsynaptic presynaptic programs promoter public health relevance response risk variant serine racemase targeted treatment transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a complex mental disorder that affects 1% of the population worldwide. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity that is associated with reductions in dendritic spine density and atrophy of the hippocampus and cortex. The cause of these synaptic disturbances likely involves a large number of risk genes and pathways, with many of the strongest candidates interacting directly with the N-methyl-D-aspartate receptor (NMDAR). Although there is significant evidence suggesting that NMDAR hypofunction contributes to the pathophysiology of schizophrenia, there is little known about the events downstream of the NMDAR that are responsible for regulating dendritic plasticity in vivo. Moreover, it is unclear whether genetic insults that perturb glutamatergic transmission by distinct molecular mechanisms impinge on convergent signaling cascades. Thus, the goals of this proposal are to utilize two mutant mouse models with impaired glutamatergic transmission, serine racemase deficient (SR-/-) and dysbindin deficient (dys-/-) mice, to identify disturbances in common final pathways regulated by NMDAR activity that contribute to impairments in hippocampal neuroplasticity, and determine whether these deficiencies can be reversed by pharmacological intervention. Our laboratory has generated a mutant mouse that lacks SR, the enzyme that converts L-serine to D-serine, which produces a 90% reduction in D-serine coupled with NMDAR hypofunction. This lack of D-serine results in decreased global NMDAR-mediated neurotransmission and reduced sensitivity to the induction of LTP in the hippocampus. My preliminary findings have shown that the hippocampal abnormalities observed in schizophrenia are recapitulated in our SR-/- mice, in that SR-/- mice have reduced: dendritic spine density on dentate granule cells (DGCs), BDNF mRNA and protein, phospho-TrkB (active form), phospho-Akt (active form), and expression of the primary, precursor, and mature transcripts of miR-132. Aim 1 of this proposal, which will be completed during the initial 2 year mentored K99 phase, will determine the molecular mechanisms responsible for the reduced miR-132 expression in SR-/- mice, test whether miR-132 dysregulation is responsible for their dendritic abnormalities, and determine whether reversing the dendritic spine abnormalities in SR-/- mice via lenti-miR-132 overexpression restores their cognitive function. Aims 2 and 3 will be completed during the subsequent 3-year independent R00 phase. Aim 2 will determine whether chronic D-serine or TrkB agonist treatment can reverse the dendritic, neurotrophic, and miR-132 expression abnormalities in SR-/- mice. Aim 3 will determine if dys-/- mice, which also have impaired glutamatergic transmission, have dendritic spine deficits that are associated with reductions in BDNF/Akt signaling and miR-132, similar to what is observed in SR-/- mice. In sum, this proposal will help to elucidate the mechanisms associated with NMDAR hypofunction that are responsible for causing the synaptic deficits and impaired neuroplasticity in schizophrenia. These novel pathways can then be targeted for therapeutic intervention in schizophrenia, as well as other brain and psychiatric disorders that exhibit dendritic spine pathologies.

描述（由申请人提供）：精神分裂症是一种复杂的精神障碍，影响全世界 1% 的人口。精神分裂症的主要病理特征之一是突触连接的扰动，这与树突棘密度的减少以及海马和皮质的萎缩有关。这些突触紊乱的原因可能涉及大量风险基因和通路，其中许多最强的候选基因和 N-甲基-D-天冬氨酸受体 (NMDAR) 直接相互作用。尽管有重要证据表明 NMDAR 功能低下会导致精神分裂症的病理生理学，但人们对 NMDAR 下游负责调节体内树突可塑性的事件知之甚少。此外，尚不清楚通过不同分子机制扰乱谷氨酸能传递的遗传损伤是否会影响汇聚信号级联。因此，本提案的目标是利用两种谷氨酸能传递受损的突变小鼠模型，即丝氨酸消旋酶缺陷型（SR-/-）和dysbindin缺陷型（dys-/-）小鼠，来识别由NMDAR活性调节的共同最终通路中导致海马神经可塑性损伤的干扰，并确定这些缺陷是否可以通过药理学逆转干涉。我们的实验室培育了一种缺乏 SR 的突变小鼠，SR 是一种将 L-丝氨酸转化为 D-丝氨酸的酶，导致 D-丝氨酸减少 90%，并伴有 NMDAR 功能减退。 D-丝氨酸的缺乏导致整体 NMDAR 介导的神经传递减少，并降低海马对 LTP 诱导的敏感性。我的初步研究结果表明，在精神分裂症中观察到的海马异常在我们的 SR-/- 小鼠中得到了重现，因为 SR-/- 小鼠减少了：齿状颗粒细胞 (DGC) 上的树突棘密度、BDNF mRNA 和蛋白、磷酸化 TrkB（活性形式）、磷酸化 Akt（活性形式）以及 miR-132 的初级、前体和成熟转录本。该提案的目标 1 将在最初 2 年指导 K99 阶段完成，将确定 SR-/- 小鼠中 miR-132 表达减少的分子机制，测试 miR-132 失调是否导致其树突异常，并确定通过 lenti-miR-132 过表达逆转 SR-/- 小鼠中的树突棘异常是否可以恢复其树突棘异常。认知功能。目标 2 和 3 将在随后的 3 年独立 R00 阶段完成。目标 2 将确定长期 D-丝氨酸或 TrkB 激动剂治疗是否可以逆转 SR-/- 小鼠的树突、神经营养和 miR-132 表达异常。目标 3 将确定谷氨酸能传递受损的 Dys-/- 小鼠是否存在与 BDNF/Akt 信号传导和 miR-132 减少相关的树突棘缺陷，类似于 SR-/- 小鼠中观察到的情况。总之，该提议将有助于阐明与 NMDAR 功能减退相关的机制，该机制导致精神分裂症中的突触缺陷和神经可塑性受损。这些新途径可以针对精神分裂症以及其他表现出树突棘病理的大脑和精神疾病进行治疗干预。