The molecular regulation of the temporal dynamics of circuit maturation is a key contributor to the emergence of normal structure–function relations. Developmental control of cortical MET receptor tyrosine kinase, expressed early postnatally in subpopulations of excitatory neurons, has a pronounced impact on the timing of glutamatergic synapse maturation and critical period plasticity. Here, we show that using a controllable overexpression (cto-Met) transgenic mouse, extending the duration of MET signaling after endogenous Met is switched off leads to altered molecular constitution of synaptic proteins, persistent activation of small GTPases Cdc42 and Rac1, and sustained inhibitory phosphorylation of cofilin. These molecular changes are accompanied by an increase in the density of immature dendritic spines, impaired cortical circuit maturation of prefrontal cortex layer 5 projection neurons, and altered laminar excitatory connectivity. Two photon in vivo imaging of dendritic spines reveals that cto-Met enhances de novo spine formation while inhibiting spine elimination. Extending MET signaling for two weeks in developing cortical circuits leads to pronounced repetitive activity and impaired social interactions in adult mice. Collectively, our data revealed that temporally controlled MET signaling as a critical mechanism for controlling cortical circuit development and emergence of normal behavior.

中文翻译：

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MET 信号的时间中断会破坏皮质回路的发育成熟并导致小鼠行为改变

电路成熟时间动力学的分子调节是正常结构-功能关系出现的关键因素。皮质 MET 受体酪氨酸激酶的发育控制，在出生后早期在兴奋性神经元亚群中表达，对谷氨酸能突触成熟和关键期可塑性的时间有显着影响。在这里，我们表明使用可控过表达 (cto-Met) 转基因小鼠，在内源性 Met 关闭后延长 MET 信号传导的持续时间会导致突触蛋白的分子结构改变，小 GTPases Cdc42 和 Rac1 的持续激活，以及持续的抑制肌动蛋白丝切蛋白的磷酸化。这些分子变化伴随着未成熟树突棘密度的增加，前额皮质第 5 层投射神经元的皮质回路成熟受损，层状兴奋性连接改变。树突棘的双光子体内成像表明，cto-Met 可增强从头形成棘突，同时抑制棘突消除。在开发皮层回路时将 MET 信号延长两周会导致成年小鼠明显的重复活动和社交互动受损。总的来说，我们的数据表明，时间控制的 MET 信号是控制皮层电路发育和正常行为出现的关键机制。在开发皮层回路时将 MET 信号延长两周会导致成年小鼠明显的重复活动和社交互动受损。总的来说，我们的数据表明，时间控制的 MET 信号是控制皮层电路发育和正常行为出现的关键机制。在开发皮层回路时将 MET 信号延长两周会导致成年小鼠明显的重复活动和社交互动受损。总的来说，我们的数据表明，时间控制的 MET 信号是控制皮层电路发育和正常行为出现的关键机制。