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Amyloid precursor protein (APP)-null mice exhibit significant deficits in motor performance, including reduced grip strength and impaired locomotion; however, the underlying neurophysiological mechanisms remain unclear. In this study, we show that conditional knockdown of APP selectively in Purkinje cells (PCs) recapitulates these motor deficits, while exogenous expression of APP in APP-null mice rescues motor function. Electrophysiological analysis revealed that APP deficiency leads to aberrant firing patterns in PCs and reduces inhibitory synaptic transmission onto neurons of the deep cerebellar nucleus (DCN). We identified a marked reduction in Nav1.6-mediated sodium currents as the key mechanism underlying abnormal action potential firing and propagation in APP-deficient PCs. Importantly, all electrophysiological and behavioral deficits were rescued by PC-specific APP reconstitution. These findings reveal a novel and essential role for APP in cerebellar motor control by regulating Nav1.6 channel activity and PC excitability.

淀粉样前体蛋白（Amyloid precursor protein, APP）敲除小鼠表现出显著的运动功能缺陷，包括抓握力下降与运动能力受损，但其背后的神经生理学机制仍不明确。本研究证实，仅在浦肯野细胞（Purkinje cells, PCs）中条件性敲低APP即可重现上述运动缺陷；而在APP敲除小鼠中外源性表达APP，则可挽救其运动功能。电生理分析显示，APP缺失会导致浦肯野细胞出现异常放电模式，并减弱小脑深部核团（deep cerebellar nucleus, DCN）神经元所接收的抑制性突触传递。我们发现，Nav1.6介导的钠电流显著降低，是APP缺失的浦肯野细胞中动作电位异常放电与传导的核心机制。值得注意的是，通过浦肯野细胞特异性重新表达APP，所有电生理与行为学缺陷均得到挽救。本研究揭示了APP在小脑运动调控中全新且不可或缺的作用，其通过调控Nav1.6通道活性与浦肯野细胞兴奋性实现该功能。