Presynaptic cytomatrix proteins and synaptogenesis

哺乳动物中枢神经系统的突触是高度特化的细胞连接，用于在神经细胞和目标细胞之间快速调节信号。中枢神经系统发育异常的突触发生和突触重组与脆性X染色体、癫痫、精神分裂症和智力低下等发育障碍密切相关。要了解不同的遗传和环境损害如何导致认知功能障碍和智力迟钝，我们需要更好地了解导致中枢神经系统突触正确组装和功能的细胞机制。这需要对突触连接成分的分子描述，以及神经元正确分类流量和定位每个成分的机制。我们对中枢神经系统突触的研究导致了许多突触连接蛋白的鉴定和表征。最近发现的一种，巴松管，是突触前细胞骨架基质的一种新成分，组装在活跃区。根据它的结构和分布，我们推测它参与了中枢神经系统突触的组装和功能。对于精神发育迟缓和认知功能障碍，我们对bason基因及其转录本的分析发现CAG扩增与亨廷顿蛋白、Ataxins和脆性X精神发育迟缓相似。此外，在神经退行性疾病、多系统萎缩中，bason基因的表达选择性增强。为了深入了解巴松管在突触前细胞骨架基质中的作用，我们建议研究巴松管在中枢神经系统突触中的运输和组装的机制。此外，我们建议通过分析小鼠巴松管基因Bsn的功能突变缺失对发育中的小鼠大脑中枢神经系统突触的结构、组装和功能的影响，来评估巴松管在突触前神经末梢中的功能。

Synapses of the mammalian CNS are highly specialized cellular junctions designed for rapid and regulated signaling between nerve cells and their targets. Abnormal synaptogenesis and synaptic reorganization in the developing CNS has been strongly correlated with developmental disorders such as fragile X, epilepsy, schizophrenia and mental retardation. Our ability to understand how different genetic and environmental insults cause cognitive dysfunction and mental retardation requires a better understanding of the cellular mechanisms that lead to the proper assembly and function of CNS synapses. This requires a molecular description of the constituents of synaptic junctions and the mechanisms used by neurons to correctly sort traffic and localized each component. Our studies of CNS synapses have led to the identification and characterization of numerous synaptic junctional proteins. One of the most recently identified, Bassoon, is a novel component of the presynaptic cytoskeletal matrix assembled at the active zone. Based on its structure on its structure and distribution, we hypothesize that it is involved in the assembly and function of CNS synapses. With regard to mental retardation and cognitive dysfunction, our analysis of the Bassoon gene and its transcripts have revealed the presence of a CAG expansion similar to these found Huntingtin, Ataxins and the Fragile X mental retardation Moreover, Basson expression is selectively enhance in a neurodegenerative disorder, multiple system atrophy. To gain insights into the role played by Bassoon in the presynaptic cytoskeletal matrix, we proposed to examine the mechanisms directing that transport and assembly of Bassoon at CNS synapses In addition we propose to assess the function of Bassoon in presynaptic nerve terminals by analyzing loss of function mutations in the mouse Bassoon gene Bsn on the structure, assembly, and function of CNS synapses in the developing mouse brain.