Brain Science Laboratory, The Research Organization of Science and Technology, Ritsumeikan University Shiga, Japan ; Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo Tokyo, Japan.
Front Neural Circuits. 2012 Nov 23;6:90. doi: 10.3389/fncir.2012.00090. eCollection 2012.
The cerebellum receives two excitatory afferents, the climbing fiber (CF) and the mossy fiber-parallel fiber (PF) pathway, both converging onto Purkinje cells (PCs) that are the sole neurons sending outputs from the cerebellar cortex. Glutamate receptor δ2 (GluRδ2) is expressed selectively in cerebellar PCs and localized exclusively at the PF-PC synapses. We found that a significant number of PC spines lack synaptic contacts with PF terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Studies with mutant mice revealed that in addition to PF-PC synapse formation, GluRδ2 is essential for synaptic plasticity, motor learning, and the restriction of CF territory. GluRδ2 regulates synapse formation through the amino-terminal domain, while the control of synaptic plasticity, motor learning, and CF territory is mediated through the carboxyl-terminal domain. Thus, GluRδ2 is the molecule that bridges synapse formation and motor learning. We found that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through cerebellin 1 (Cbln1) mediates PF-PC synapse formation. The synaptogenic triad is composed of one molecule of tetrameric GluRδ2, two molecules of hexameric Cbln1 and four molecules of monomeric NRXN. Thus, GluRδ2 triggers synapse formation by clustering four NRXNs. These findings provide a molecular insight into the mechanism of synapse formation in the brain.
小脑接收两种兴奋性传入，即 climbing fiber (CF) 和 mossy fiber-parallel fiber (PF) 通路，它们都汇聚到浦肯野细胞 (PC) 上，浦肯野细胞是唯一从小脑皮层发出输出的神经元。谷氨酸受体 δ2 (GluRδ2) 选择性地在小脑 PC 中表达，并专门定位于 PF-PC 突触。我们发现，大量的 PC 棘突缺乏与 PF 末梢的突触接触，并且在常规和条件性 GluRδ2 敲除小鼠中，一些残留的 PF-PC 突触在前后突触特化之间存在不匹配。对突变体小鼠的研究表明，除了 PF-PC 突触形成之外，GluRδ2 对于突触可塑性、运动学习和 CF 领域的限制也是必不可少的。GluRδ2 通过氨基末端结构域调节突触形成，而突触可塑性、运动学习和 CF 领域的控制则通过羧基末端结构域介导。因此，GluRδ2 是连接突触形成和运动学习的分子。我们发现，通过小脑素 1 (Cbln1)，突触后 GluRδ2 和突触前神经连接蛋白 (NRXNs) 的跨突触相互作用介导了 PF-PC 突触形成。突触形成三联体由一个四聚体 GluRδ2 分子、两个六聚体 Cbln1 分子和四个单体 NRXN 分子组成。因此，GluRδ2 通过聚类四个 NRXNs 触发突触形成。这些发现为大脑中突触形成的机制提供了分子见解。
