Zhang Jianling, Watanabe Takaki, Miyazaki Taisuke, Yamasaki Miwako, Konno Kohtarou, Okuno Yuto, Matsuyama Kyoko, Noro Takayuki, Watanabe Masahiko, Uesaka Naofumi, Kano Masanobu
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo, Tokyo 113-0033, Japan.
iScience. 2025 May 26;28(6):112746. doi: 10.1016/j.isci.2025.112746. eCollection 2025 Jun 20.
Eliminating redundant synapses formed around birth is essential for shaping functionally mature neural circuits during postnatal development. Each Purkinje cell (PC) in the neonatal mouse cerebellum receives synaptic inputs from multiple climbing fibers (CFs). Only one CF is strengthened and extends its innervation over PC dendrites, whereas the other CFs are eventually pruned during postnatal development. These events are believed to require proper gene expression, but the underlying mechanisms are not yet understood. Here, we report that the transcription factor ZFP64 in PCs mediates part of CF synapse elimination events presumably downstream of P/Q-type voltage-dependent Ca channels (P/Q-VDCCs). PC-specific knockdown (KD) of ZFP64 during postnatal development delayed the elimination of redundant CF synapses and the dendritic extension of CF innervation. The KD of semaphorin 3A (Sema3A) in PCs partially restored the effects of ZFP64 or P/Q-VDCC KD. We propose that ZFP64 promotes developmental CF synapse elimination by regulating Sema3A expression.
消除出生前后形成的冗余突触对于在出生后发育过程中塑造功能成熟的神经回路至关重要。新生小鼠小脑中的每个浦肯野细胞（PC）都从多条攀缘纤维（CF）接收突触输入。只有一条CF得到加强并在PC树突上扩展其支配，而其他CF最终在出生后发育过程中被修剪。这些事件被认为需要适当的基因表达，但其潜在机制尚不清楚。在这里，我们报告PC中的转录因子ZFP64介导了部分CF突触消除事件，可能在P/Q型电压依赖性钙通道（P/Q-VDCCs）下游。出生后发育期间PC特异性敲低（KD）ZFP64延迟了冗余CF突触的消除和CF支配的树突扩展。PC中信号素3A（Sema3A）的KD部分恢复了ZFP64或P/Q-VDCC KD的作用。我们提出ZFP64通过调节Sema3A表达促进发育性CF突触消除。
