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.
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