The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo.

中文翻译：

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TrkC-PTPσ 复合物通过突触蛋白磷酸化控制突触成熟和焦虑回避。


突触前末梢和突触后末梢的精确组织对于大脑中的正常突触功能至关重要。除了作为神经营养因子 3 受体酪氨酸激酶的经典作用外，突触后 TrkC 还通过与突触前受体型酪氨酸磷酸酶 PTPσ 相互作用来促进兴奋性突触组织。为了将 TrkC 的突触组织功能与其作为神经营养因子 3 受体的作用分离，我们生成了携带 TrkC 点突变的小鼠，这些突变选择性地消除 PTPσ 结合。突变小鼠的兴奋性突触具有异常的突触囊泡聚集和突触后致密伸长，更无声的突触，更少的活动突触，此外还表现出增强的基础传递和受损的释放概率。除了这些表型外，我们还观察到异常的突触蛋白磷酸化，但神经营养因子信号通路没有差异。与将这些异常磷酸化蛋白与神经精神疾病联系起来的报道一致，突变的 TrkC 敲入小鼠表现出社交反应受损和回避行为增加。因此，通过调节突触蛋白磷酸化，TrkC-PTPσ 复合物对体内兴奋性突触的成熟至关重要，但对兴奋性突触的形成至关重要。