谱系依赖神经微环路形成的分子机制

Dysfunctional neuronal connectivity has been implicated in many neurological disorders, such as autism spectrum disorders (ASD). Except social interaction difficulties, communication challenges and a tendency to engage in repetitive behaviors, ASD also affect emotional control, perception and certain type of memories in patients. Synaptic specificity is the basis of forming neural microcircuits, however, the underlying molecular mechanism remains largely unknown. An increasing amount of data show that neurons specifically connect with each other to assemble specific neural circuits with specific physiological functions. As a small scale of brain circuits, the neural microcircuits offer a very attractive intermediate for us to study the brain, which contains a much more complex network. We will take advantage of the newly identified lineage-dependent microcircuit in which sister cells originated from a common progenitor preferentially form synapses, to investigate the mechanism how cells can recognize each other and then form synapses in neural microcircuits. Our preliminary data showed that clustered protocadherins (PCDH), ASD risking factors, are the basis of neuronal diversification. PCDH are the largest subfamily of homophilic cell adhesion molecules, which play important roles in synapse formation. Because of the above reasons, we will combine several complementary techniques, such as multiple whole-cell patch clamp recordings, manipulating protein expression in transgenic mice and single-cell RT-PCR to identify the roles of protocadherin in synaptic specificity. Successful completion of our study will not only result in a comprehensive understanding of the specification of synapse formation, but also provide a new insight into the pathogenesis of ASD at the neural circuit level. It should also have important implications for the prevention and treatment of unreliable perception and emotional control in ASD.

神经环路形成的异常会导致自闭症等多种神经性疾病。自闭症患者在情感控制，对外感知以及记忆方面等有异于常人。突触特异性是神经环路形成的基础，但其分子机制却非常不清楚。众多数据表明神经元间会特异性地彼此相连组成特定的神经环路，参与特定的生理功能。这些相对简单的神经环路给我们提供了一个认识复杂大脑的平台。我们将充分利用新近鉴定的谱系依赖微环路中姊妹细胞能够优先形成突触这个现象来研究突触特异性，以阐明神经环路中神经元间是如何特异性识别对方，进而形成突触。我们初步数据表明自闭症风险因子成簇性原钙粘蛋白是神经元多样化的基础，这类分子嗜同相吸，参与突触形成。我们将结合多通道全细胞膜片钳记录、转基因小鼠和单细胞RT-PCR等多种主要实验手段来验证该蛋白在突触特异性中的作用。该项目的成功实施将极大增强我们对大脑中神经环路组装机理的了解，同时也能够帮助理解自闭症患者为何会具有情感控制和对外感知不稳定等症状。