PSD-95 deficiency alters glutamatergic synapses during development in the prefrontal cortex

PSD-95 缺乏会改变前额皮质发育过程中的谷氨酸突触

基本信息

批准号：
10595661
负责人：
Austin Coley
金额：
$ 6.86万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-28 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10595661
关键词：
AMPA Receptors Acids Adolescence Adolescent Adult Affect Anterior Behavior Behavior assessment Behavioral Brain region Calcium Cells Cognition Cognitive Data Dendritic Spines Development Emotional Excitatory Synapse Exhibits Faculty Functional disorder Future Teacher Gene Targeting Genes Glutamate Receptor Glutamates Goals Hippocampus Image Impairment Ipsilateral Knockout Mice Link Measures Medial Mediating Mentors Microscopy Missense Mutation Modeling Molecular Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurodevelopmental Deficit Neurodevelopmental Disorder Neurons Neurosciences Optics Patch-Clamp Techniques Pathology Patients Phase Physiological Pilot Projects Play Positioning Attribute Postdoctoral Fellow Postsynaptic Membrane Prefrontal Cortex Property Protein Subunits Publications Publishing Regulation Reporting Research Resolution Role Scaffolding Protein Schizophrenia Short-Term Memory Social Interaction Solid Synapses Techniques Testing Thalamic structure Time Whole-Cell Recordings adeno-associated viral vector age related aspartate receptor autism spectrum disorder cognitive function critical period executive function exome sequencing flexibility frontal lobe hippocampal pyramidal neuron insight lectures mouse model nervous system disorder neuropsychiatric disorder optogenetics postnatal postsynaptic postsynaptic density protein presynaptic density protein 95 professor protein expression receptor recruit response social symposium synaptic function synaptogenesis trafficking transmission process trend

项目摘要

Project Summary/Abstract Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein located at the dendritic spines of excitatory synapses and is involved in the recruitment, trafficking, and stabilization of N-methyl-D- aspartic acid receptors (NMDAR’s) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR's) to the postsynaptic membrane during synaptic maturation. Previous studies have shown that within the hippocampus, PSD-95 deficiency causes “silent synapse” formation that may be associated with the pathology observed in the neurological disorders of schizophrenia (SCZ) and autism. However, the effects of PSD-95 deficiency within the prefrontal cortex (PFC), a brain region with delayed maturation, have yet to be investigated. The PFC, located anterior of the frontal lobe, is responsible for cognition, working memory, emotional control, and sociability. It is also highly associated with neurodevelopmental disorders, especially schizophrenia. We hypothesize that PSD-95 deficiency will disrupt synaptic maturation in an age-dependent manner due to an increase in NMDAR/AMPAR-glutamatergic transmission that leads to impairments in PFC development and function. In this study we use a PSD-95-/- mouse to model PSD-95 deficiency and investigate NMDA and AMPA-receptor properties within the medial prefrontal cortex (mPFC). We explore protein expression levels of NMDAR and AMPAR-subunits and other relevant scaffolding proteins. Additionally, we examine NMDAR/AMPAR-transmission to characterize silent synapses, and accordingly, we will examine working memory function and social interaction to measure social novelty and exploration. Furthermore, based on our preliminary finding of increased NMDA/AMPA ratio in corticocortical afferents, we will examine the major inputs of the mPFC − the mediodorsal thalamus (MD), which is responsible for the development and function of the mPFC via reciprocal connections mediated by glutamatergic transmission. We further hypothesize that PSD-95 deficiency will impair thalamocortical projections via disrupted glutamatergic transmission, resulting in afferent-specific changes in synaptic function and neurodevelopmental deficits of the mPFC that lead to physiological and behavioral dysfunctions. We will inject an adeno-associated virus (AAV) vector expressing channelrhodopsin-2 (ChR2) within the MD and use optogenetics to specifically activate MD inputs to mPFC to record excitatory postsynaptic currents. Together, this data will provide a greater understanding of how PSD-95 affects the glutamate receptor composition and transmission as it relates to mPFC development and function.

项目概要/摘要突触后密度蛋白 95 (PSD-95) 是一种位于树突的高度丰富的支架蛋白兴奋性突触的棘，参与 N-甲基-D- 的招募、运输和稳定天冬氨酸受体 (NMDAR) 和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体先前的研究表明，在突触成熟过程中，（AMPAR）会进入突触后膜。在海马体中，PSD-95 缺乏会导致“沉默突触”的形成，这可能与然而，在精神分裂症（SCZ）和自闭症的神经系统疾病中观察到的病理学影响。前额皮质 (PFC) 内的 PSD-95 缺陷（PFC 是一个延迟成熟的大脑区域）尚未得到解决。研究发现，前额皮质位于额叶前部，负责认知、工作记忆、它也与神经发育障碍密切相关，尤其是神经发育障碍。我们勇敢地承认 PSD-95 缺乏会破坏年龄依赖性的突触成熟。由于 NMDAR/AMPAR 谷氨酸传输增加导致 PFC 损伤在本研究中，我们使用 PSD-95-/- 小鼠来模拟 PSD-95 缺陷并进行研究。我们探索内侧前额皮质 (mPFC) 内的 NMDA 和 AMPA 受体特性。 NMDAR 和 AMPAR 亚基以及其他相关支架蛋白的表达水平。检查 NMDAR/AMPAR 传输来表征沉默突触，相应地，我们将检查此外，还以工作记忆功能和社交互动来衡量社交新颖性和探索性。根据我们初步发现皮质传入神经中 NMDA/AMPA 比率增加，我们将检查 mPFC 的主要输入 - 内侧丘脑 (MD)，负责发育和我们进一步研究了 mPFC 通过谷氨酸能传递介导的相互连接的功能。 PSD-95 缺乏症会通过谷氨酸能破坏而损害丘脑皮质投射传递，导致突触功能的传入特异性变化和神经发育缺陷导致生理和行为功能障碍的 mPFC 我们将注射腺相关病毒 (AAV)。 MD 内表达通道视紫红质 2 (ChR2) 的载体，并使用光遗传学特异性激活 MD 输入 mPFC 来记录兴奋性突触后电流，这些数据将提供更大的数据。了解 PSD-95 如何影响谷氨酸受体的组成和传输，因为它与 mPFC 的发育和功能。