Mechanisms of Synapse Remodeling of Cortical GABAergic Interneurons

摘要 在发育过程中，兴奋性和抑制性(E/I)连接建立了适当的平衡 并通过突触可塑性进行调节，但在我们的大脑中 了解这一过程是如何被监管的。没有进一步描述发育中突触的特征 重塑，我们对与GABA能抑制连接相关的神经精神障碍的理解 精神分裂症和自闭症等干扰是有限的。这项研究的目的是描述 在前额叶皮质建立E/I平衡的分子机制，这可能识别新的靶点 治疗E/I平衡改变的疾病。这项提案的具体目标是定义一个 限制GABA能篮状中间神经元与锥体神经元抑制性联系的机制。 这一提议的中心假设是神经细胞黏附分子NCAM和酪氨酸激酶EphA3 形成突触前受体复合体促进突触周围突触的消除 在出生后早期前额叶皮质(PFC)的发育过程中。我还假设形成了 PFC出生后发育后期的周围神经网终止NCAM/EphA3介导的篮子 细胞重塑。为了解决这些假设，我将(1)描述NCAM/EphA3结合的重要性 通过在功能分析中使用非结合突变体，包括受体聚集，下游EphA3信号， 和生长锥体塌陷，(2)确定Neuran是否竞争性地抑制NCAM/EphA3的结合，(3) 建立新的小鼠模型，有条件地删除皮质神经元中的NCAM并评估周围区 使用双光子活体成像技术检测突触重构，以及(4)检测三叉神经节抑制篮筐重构的作用 脑片中的细胞。这些研究的结果可望对我们理解 出生后PFC和Can区GABA能中间神经元突触重构的新分子机制 洞察涉及E/I平衡紊乱的神经性疾病的病因。

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.