Mechanisms of Synapse Remodeling of Cortical GABAergic Interneurons

皮质 GABA 能中间神经元突触重塑机制

• 批准号: 9306700
• 负责人: Chelsea Suzanne Sullivan
• 金额: $ 4.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-04-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306700
• 关键词: Acute; Address; Adhesions; Area; Autistic Disorder; Binding; Biological Assay; Bipolar Disorder; Brain; CSPG3 gene; Cell Adhesion Molecules; Cell surface; Cognitive deficits; Complex; Data; Development; Disease; Equilibrium; Etiology; Event; Extracellular Domain; Goals; Growth Cones; Image; Immunoglobulins; Inhibitory Synapse; Interneurons; Knockout Mice; Ligands; Link; LoxP-flanked allele; Medial; Mediating; Molecular; Mus; Mutant Strains Mice; Myoepithelial cell; NCAM1 gene; Neural Cell Adhesion Molecules; Neurites; Neurodevelopmental Disorder; Neurons; Output; Parvalbumins; Play; Prefrontal Cortex; Presynaptic Receptors; Process; Property; Protein Tyrosine Kinase; Pyramidal Cells; Receptor Protein-Tyrosine Kinases; Regulation; Reporter; Research; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Slice; Synapses; Synaptic plasticity; Testing; conditional mutant; experimental study; hippocampal pyramidal neuron; in vivo; insight; mouse development; mouse model; mutant; nerve supply; nervous system disorder; neuropsychiatric disorder; novel; postnatal; postsynaptic; premature; presynaptic; prevent; receptor; synaptogenesis; two-photon

Abstract Establishment of a proper balance of excitatory and inhibitory (E/I) connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity, but there are fundamental gaps in our understanding of how this process is regulated. Without further characterization of developmental synapse remodeling, our understanding of neuropsychiatric disorders associated with GABAergic inhibitory connection disruption such as schizophrenia and autism is limited. The purpose of this research is to characterize molecular mechanisms that establish E/I balance in the prefrontal cortex, which may identify novel targets for treatment of disorders in which E/I balance is altered. The specific goal of this proposal is to define a mechanism for limiting inhibitory connections between GABAergic basket interneurons and pyramidal neurons. The central hypothesis of this proposal is that neural cell adhesion molecule NCAM and tyrosine kinase EphA3 form a presynaptic receptor complex for postsynaptic ephrinA5 to promote elimination of perisomatic synapses during early postnatal development of the prefrontal cortex (PFC). I also hypothesize that formation of perineuronal nets (PNNs) in later postnatal development of the PFC terminates NCAM/EphA3-mediated basket cell remodeling. To address these hypotheses, I will (1) characterize the importance of NCAM/EphA3 binding by using non-binding mutants in functional assays including receptor clustering, downstream EphA3 signaling, and growth cone collapse, (2) determine whether Neurocan competitively inhibits binding of NCAM/EphA3, (3) develop novel mouse models to conditionally delete NCAM in cortical neurons and assess perisomatic synapse remodeling using live two-photon imaging, and (4) test whether PNNs prevent remodeling of basket cells in brain slices. The findings of these studies are expected to be of great value to our understanding of novel molecular mechanisms of synapse remodeling of GABAergic interneurons in postnatal PFC and could provide insight into the etiology of neurological disorders involving E/I balance disruption.

摘要 兴奋性和抑制性（E/I）连接的适当平衡的建立是在发育过程中实现的 大脑皮层网络，并通过突触可塑性进行调整，但在我们的大脑皮层网络中存在根本性的差距。 了解这个过程是如何被管理的。如果没有进一步的发育突触特征 重塑，我们对与GABA能抑制连接相关的神经精神疾病的理解 精神分裂症和孤独症等精神分裂症的发病率有限。这项研究的目的是描述 在前额叶皮层建立E/I平衡的分子机制，这可能会发现新的靶点， 治疗E/I平衡改变的疾病。该提案的具体目标是确定一个 限制GABA能篮状中间神经元和锥体神经元之间的抑制性连接的机制。 该建议的中心假设是神经细胞粘附分子NCAM和酪氨酸激酶EphA 3 形成突触后ephrinA 5的突触前受体复合物以促进体周突触的消除 在出生后早期的前额叶皮层（PFC）发育过程中。我还假设， 在PFC的后期出生后发育中的神经元周网（PNNs）终止NCAM/EphA 3介导的篮 细胞重塑为了解决这些假设，我将（1）表征NCAM/EphA 3结合的重要性， 通过在包括受体聚集，下游EphA 3信号传导， 和生长锥塌陷，（2）确定Neurocan是否竞争性抑制NCAM/EphA 3的结合，（3） 开发新的小鼠模型，以有条件地删除皮层神经元中的NCAM，并评估周围神经元的功能。 使用活体双光子成像检测突触重塑，以及（4）测试PNN是否阻止篮的重塑 脑切片中的细胞。这些研究的结果对我们了解 出生后PFC中GABA能中间神经元突触重塑的新分子机制， 提供对涉及E/I平衡破坏的神经系统疾病的病因学的深入了解。