大脑神经回路的正确形成有赖于准确的神经树突形态形成和突触发育。神经回路功能缺陷导致许多神经精神系统疾病，包括精神分裂症。调节树突发育的机制目前所知有限。以往研究表明，Dasm1，一个新的免疫球蛋白超家族成员，特异性地调节树突的形态发生和谷氨酸能神经突触的成熟。Dasm1功能缺失导致海马神经元树突树分支简化以及谷氨酸能神经传递缺陷。Dasm1基因定位于与精神分裂症遗传连锁相关的染色体1q22-23。大量证据表明精神分裂症中谷氨酸能神经系统受损，树突棘密度减低，异常神经回路形成，而分子机制尚不明了。基于Dasm1介导的生理过程，我们猜测Dasm1功能失调可能与精神分裂症的发生密切相关。本项目拟采用转基因小鼠，实时成像技术，生化和电生理等实验手段进一步揭示Dasm1特异性调控树突形态发育和突触成熟的分子机制，并试图探索其与精神分裂症之间的潜在关联。本项目的完成有可能为治疗精神分裂症提供新的思路。

Proper dendrite morphogenesis and synapse development is essential for neuronal circuit assembly and function in the brain. Defects in dendrite morphogenesis and synapse development onto dendrites will result in malfunction of neuronal circuits and are often linked to neurological and psychological disorders, such as mental retardation, Alzheimer's diseases, autism, and schizophrenia. However, molecular machineries that control dendrite development are not well understood. Recently, we identified a novel immunoglobulin superfamily (IgSF) member, Dendrite arborization and synapse maturation 1 (Dasm1), which plays a critical role in regulating dendrite, but not axon, morphogenesis and glutamatergic synapse maturation. Disruption of its function leads to reduced dendritic arbor and impaired glutamatergic neurotransmission in hippocampal neurons. The Dasm1 gene locates in chromosome 1q22-23 region, which is indicated as a positive linkage of schizophrenia. Schizophrenia is a neurodevelopmental disorder that afflicts ~1% of the world population. Many evidences suggest the critical role of the glutamate system dysfunction in schizophrenia. Anatomical and physiological studies reveal decreased dendritic spine density, altered glutamatergic neurotransmission, and abnormal neuronal circuits in the brains of schizophrenics. However, the molecular basis for these anomalies is unclear. Taken together, these data raises the possibility that the Dasm1 malfunction might be related to schizophrenia. In this proposal, I plan to: 1). To understand functional specificity of Dasm1 in regulating dendrite morphogenesis; 2). To uncover extracellular and intracellular signaling pathways that mediate Dasm1 function; 3). To generate Dasm1 knockout mice to perform in-depth functional analysis of Dasm1 in dendrite morphogenesis and synapse development and plasticity in vivo. and to explore its link to schizophrenia. I will employ a multidiscipline approaches encompassing mouse genetics, time-lapse imaging, biochemistry and electrophysiology and use rodent as a model to pursue these specific aims above. In summary, the proposed studies in this application will not only allow us to define key machineries that control dendrite morphogenesis and synapse development, but may also facilitate our understanding of neuronal circuit development and function in the brain under normal and disease conditions and provide new therapeutic ideas for treatments for patients with various neurological disorders including schizophrenia.