VGLUT2 Transmission in Prefrontal Cortex and Working Memory

前额皮质和工作记忆中的 VGLUT2 传输

基本信息

批准号：
8700767
负责人：
JEFFREY D ERICKSON
金额：
$ 21.89万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700767
关键词：
Adolescent Adult Attention Behavioral Development Disinhibition Equilibrium Exhibits Feedback Frequencies Functional disorder Glutamates Goals Hippocampus (Brain)Immunofluorescence Immunologic Impaired cognition In Vitro Interneurons Knockout Mice Knowledge Lead Learning Measures Medial Mediating Memory Memory impairment Mus N-Methylaspartate Neurons Outcome Parvalbumins Patients Physiological Prefrontal Cortex Prevention Primates Receptor Signaling Recurrence Reversal Learning Rodent Role Schizophrenia Short-Term Memory Slice Synapses Synaptic Transmission System Testing Therapeutic Transgenic Mice aspartate receptor base developmental disease endophenotype gamma-Aminobutyric Acid hippocampal pyramidal neuron improved in vivo insight neocortical postsynaptic presynaptic prevent public health relevance selective expression transmission process treatment strategy vesicular glutamate transporter 2

项目摘要

Abstract. Schizophrenia is a developmental disorder that is hypothesized to include alterations in glutamatergic function, aberrant N-methyl-D-aspartic acid receptor (NMDAR) signaling and altered excitatory/inhibitory (E/I) balance in the medial prefrontal cortex (mPFC). A critical barrier to progress in improving strategies for the treatment and prevention of schizophrenia is a lack of understanding of the role of presynaptic glutamate release onto GABAergic interneurons by intrinsic cortical vesicular glutamate transporter-2 (VGLUT2) synapses in regulating E/I balance and how this may impact the maturation of PV- containing interneurons. Our goal is to improve strategies for the treatment and prevention of schizophrenia by developing and providing an understanding of the role and influence of VGLUT2-mediated glutamate release on the dysfunction of the PV-inhibitory system. Our central hypothesis is that VGLUT2 provides glutamate to neocortical PV+ inhibitory interneurons in the mPFC that is important for the maturation of excitatory/inhibitory (E/I) balance and to working memory. Our objectives are to (1) establish that functional VGLUT2 synapses target the PV+ interneuronal system in mPFC in vivo and in vitro, (2) demonstrate that the loss of VGLUT2 synapses decreases glutamate release at E-I synapses and suppresses inhibitory transmission, and (3) show that conditional VGLUT2 knockout (KO) mice display deficits in working memory. Our expected outcomes will be (1) an understanding that intrinsic cortical VGLUT2 synapses are relevant to E/I balance because they target recurrent inhibitory feedback neurons and exhibit activity-dependent release of glutamate, (2) the knowledge that loss of intrinsic cortical VGLUT2 expression in conditional VGLUT2 KO mice leads to a reduction in GAD67 in PV+ interneurons and suppresses inhibitory synaptic transmission onto pyramidal neurons, and (3) to affirm that VGLUT2-encoded transmission in corticolimbic circuits is critical to working memory. The impact of these results on strategies for treating and preventing schizophrenia that our outcomes will provide is an important step towards therapeutic insight into the cognitive impairment associated with schizophrenia and an understanding of the role and influence of VGLUT2-mediated release on the maturation of the PV-interneuronal system and E/I balance. Aim 1 will test the hypothesis that intrinsic cortical VGLUT2 synapses are relevant to E/I balance because a) they target PV+ GABAergic interneurons, b) they exhibit activity-dependent release of glutamate, and c) their loss suppresses inhibitory synaptic transmission in the mPFC. We will utilize GAD67gfp+ transgenic mice that selectively express EGFP in PV+ interneurons for immunofluorescence and electrophysiologic studies. Aim 2 will test the hypothesis that VGLUT2-encoded excitatory transmission in corticolimbic circuits during development is critical to working memory in adults, by assessing working memory function using the continuous delayed alternation task in a T-maze in two lines of mice where VGLUT2 inactivation occurs early in development and in adolescent mice.

抽象的。精神分裂症是一种发育障碍，假设包括谷氨酸功能、异常的 N-甲基-D-天冬氨酸受体 (NMDAR) 信号传导和改变内侧前额皮质 (mPFC) 的兴奋/抑制 (E/I) 平衡。取得进展的一个关键障碍改善精神分裂症治疗和预防策略的关键是缺乏对精神分裂症作用的了解突触前谷氨酸通过内在皮质囊泡谷氨酸释放到 GABA 能中间神经元上转运蛋白 2 (VGLUT2) 突触调节 E/I 平衡以及这如何影响 PV-的成熟含有中间神经元。我们的目标是通过以下方式改进精神分裂症的治疗和预防策略：开发并提供对 VGLUT2 介导的谷氨酸释放的作用和影响的理解 PV 抑制系统功能障碍。我们的中心假设是 VGLUT2 提供谷氨酸 mPFC 中的新皮质 PV+ 抑制性中间神经元，对于神经元的成熟很重要兴奋/抑制（E/I）平衡和工作记忆。我们的目标是 (1) 建立功能性的 VGLUT2 突触在体内和体外以 mPFC 中的 PV+ 中间神经元系统为目标，(2) 证明 VGLUT2 突触的缺失会减少 E-I 突触的谷氨酸释放并抑制抑制 (3) 显示条件性 VGLUT2 敲除 (KO) 小鼠表现出工作记忆缺陷。我们的预期结果将是 (1) 了解内在皮质 VGLUT2 突触与 E/I 平衡，因为它们针对周期性抑制反馈神经元并表现出活性依赖性释放谷氨酸，(2) 条件性 VGLUT2 KO 小鼠中内在皮质 VGLUT2 表达丧失的知识导致 PV+ 中间神经元中 GAD67 的减少并抑制抑制性突触传递锥体神经元，以及（3）确认皮质边缘回路中 VGLUT2 编码的传输对于工作记忆。这些结果对治疗和预防精神分裂症策略的影响结果将提供对认知障碍相关的治疗洞察的重要一步患有精神分裂症并了解 VGLUT2 介导的释放对精神分裂症的作用和影响 PV 间神经元系统的成熟和 E/I 平衡。目标 1 将检验以下假设：内在皮质 VGLUT2 突触与 E/I 平衡相关，因为 a) 它们针对 PV+ GABA 能中间神经元，b) 它们表现出谷氨酸的活性依赖性释放，并且c）它们的损失抑制了抑制性突触传递 mPFC。我们将利用在 PV+ 中间神经元中选择性表达 EGFP 的 GAD67gfp+ 转基因小鼠免疫荧光和电生理学研究。目标 2 将测试 VGLUT2 编码的假设发育过程中皮质边缘回路的兴奋性传递对于成人的工作记忆至关重要，使用 T 迷宫中的两行连续延迟交替任务评估工作记忆功能 VGLUT2 失活发生在发育早期和青春期小鼠中的小鼠。