Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Mol Brain. 2023 Jul 24;16(1):61. doi: 10.1186/s13041-023-01048-4.
Changes in neural activity induced by learning and novel environments have been reported to lead to the formation of new synapses in the adult brain. However, the underlying molecular mechanism is not well understood. Here, we show that Purkinje cells (PCs), which have established adult-type monosynaptic innervation by climbing fibers (CFs) after elimination of weak CFs during development, can be reinnervated by multiple CFs by increased expression of the synaptic organizer C1ql1 in CFs or Bai3, a receptor for C1ql1, in PCs. In the adult cerebellum, CFs are known to have transverse branches that run in a mediolateral direction without forming synapses with PCs. Electrophysiological, Ca-imaging and immunohistochemical studies showed that overexpression of C1ql1 or Bai3 caused these CF transverse branches to elongate and synapse on the distal dendrites of mature PCs. Mature PCs were also reinnervated by multiple CFs when the glutamate receptor GluD2, which is essential for the maintenance of synapses between granule cells and PCs, was deleted. Interestingly, the effect of GluD2 knockout was not observed in Bai3 knockout PCs. In addition, C1ql1 levels were significantly upregulated in CFs of GluD2 knockout mice, suggesting that endogenous, not overexpressed, C1ql1-Bai3 signaling could regulate the reinnervation of mature PCs by CFs. Furthermore, the effects of C1ql1 and Bai3 overexpression required neuronal activity in the PC and CF, respectively. C1ql1 immunoreactivity at CF-PC synapses was reduced when the neuronal activity of CFs was suppressed. These results suggest that C1ql1-Bai3 signaling may mediate CF synaptogenesis in mature PCs, potentially in concert with neuronal activity.
学习和新环境引起的神经活动变化已被报道导致成年大脑中新突触的形成。然而，其潜在的分子机制尚不清楚。在这里，我们表明，在发育过程中通过消除弱的 climbing fibers（CFs）而建立了成年型单突触支配的浦肯野细胞（PCs），可以通过 CFs 中突触组织者 C1ql1 的表达增加或 PCs 中 C1ql1 的受体 Bai3 的表达增加而被多个 CFs 重新支配。在成年小脑，已知 CFs 具有横向分支，它们沿内外方向运行而不与 PCs 形成突触。电生理、Ca 成像和免疫组织化学研究表明，C1ql1 或 Bai3 的过表达导致这些 CF 横向分支伸长并与成熟 PCs 的远端树突形成突触。当对于颗粒细胞和 PCs 之间的突触维持至关重要的谷氨酸受体 GluD2 缺失时，成熟 PCs 也被多个 CF 重新支配。有趣的是，GluD2 敲除的效果在 Bai3 敲除的 PCs 中没有观察到。此外，在 GluD2 敲除小鼠的 CF 中 C1ql1 水平显著上调，表明内源性的，而不是过表达的 C1ql1-Bai3 信号可以调节 CF 对成熟 PCs 的再支配。此外，C1ql1 和 Bai3 的过表达的作用分别需要 PC 和 CF 中的神经元活性。当抑制 CF 的神经元活性时，CF-PC 突触处的 C1ql1 免疫反应性降低。这些结果表明，C1ql1-Bai3 信号可能介导成熟 PCs 中的 CF 突触发生，可能与神经元活性协同作用。
