MODULATION OF GLUTAMATE SYNAPSES IN NEONATAL CORTEX

皮层突触结构完整性的改变已在多种形式的智力迟钝中得到证实，包括那些可归因于染色体异常（例如，唐氏综合征，脆性X染色体，天使综合征，Praeder-Willi综合征，威廉综合征），产前暴露于致畸物（例如，乙醇）和严重的新生儿癫痫发作。这些结构缺陷大多位于树突棘上的突触，谷氨酸能输入的位置，它们可以发生在人类和动物模型中。在正常发育过程中，这些谷氨酸能皮质突触的效率、分布和结构受到经验、神经活动和其他神经递质（如血清素）的实质性调节。（干扰正常的谷氨酸能突触传递可导致癫痫发作、神经毒性和皮质结构异常的发展）。这个项目是一个多方面的研究：(1)皮层谷氨酸突触的初始分子组装（项目一）；(2)发育过程中传递行为相关信号的能力（项目二）；(3)其在出生后发育过程中由(i)两种相邻的细胞类型-皮质下白质神经元和星形胶质细胞，（ii）调节剂，5-羟色胺（5-HT）和一氧化氮，（iii） 5-羟色胺和谷氨酸神经递质转运体（项目iii， IV和V）调节。一个发育神经生物学成像核心（Core B）和一个管理/项目开发核心（Core A）神经生物学成像核心（Core B）和一个管理/项目开发核心（Core A）将提供关键服务，并促进项目之间的协同作用。通过了解这些突触的分子组成，在生理背景下的功能特性，以及它们在正常新生儿中被内在门控通路修饰的机制，本项目将为理解发育中的谷氨酸突触对MR中损害突触结构和功能的趋同过程的敏感性提供实质性的新基础。

Altered structural integrity of cortical synapses has been demonstrated in a variety of forms of mental retardation, including those attributable to chromosomal abnormalities (e.g., Down Syndrome, Fragile X, Angelman Syndrome, Praeder-Willi Syndrome, William's Syndrome), prenatal exposure to teratogens (e.g., ethanol) and severe neonatal seizures. Most of these structural defects are at synapses located on dendritic spines, sites of glutamatergic input, and they can occur in humans and animal models. The efficiency, distribution, and structure of these glutamatergic cortical synapses undergo substantial modulation by experience, neural activity, and other neurotransmitters such as serotonin during normal development. (Interference with normal glutamatergic synaptic transmission can lead to seizures, neurotoxicity, and development of abnormal cortical architecture). This program project is a multi-faceted inquiry into (1) the initial molecular assembly of the cortical glutamate synapse (Project I); (2) its capacity for transferring behaviorally relevant signals during development (Project II); and (3) its modulating during postnatal development by (i) two neighboring cell types-subcortical white matter neurons and astrocytes, (ii) the modulators, serotonin (5-HT) and nitric oxide, and (iii) the 5-HT and glutamate neurotransmitter transporters (Projects III, IV, and V). A Developmental Neurobiology Imaging Core (Core B) and an Administration/Project Development Core (Core A) Neurobiology Imaging Core (Core B) and an Administration/Project Development Core (Core A) will provide critical services and will promote synergy among projects. By learning the molecular components of these synapses, their functional properties in a physiological context, and the mechanisms of their modification by intrinsic gating pathway in the normal neonate, this project will provide a substantial new basis for understanding the sensitivity of developing glutamate synapses to the convergent processes that compromise synaptic structure and function in MR.