Abstract:
Kainate (KA)-type glutamate receptors (KARs) are implicated in various neuropsychiatric and neurological disorders through their ionotropic and metabotropic actions. However, compared to AMPA- and NMDA-type receptor functions, many aspects of KAR biology remain incompletely understood. Our study demonstrates an important role of KARs in organizing climbing fiber (CF)-Purkinje cell (PC) synapses and synaptic plasticity in the cerebellum, independently of their ion channel or metabotropic functions. The amino-terminal domain (ATD) of the GluK4 KAR subunit binds to C1ql1, provided by CFs, and associates with Bai3, an adhesion-type G protein-coupled receptor expressed in PC dendrites. Mice lacking GluK4 exhibit no KAR-mediated responses, reduced C1ql1 and Bai3 levels, and fewer CF-PC synapses, along with impaired long-term depression and oculomotor learning. Remarkably, introduction of the ATD of GluK4 significantly improves all these phenotypes. These findings demonstrate that KARs act as synaptic scaffolds, orchestrating synapses by forming a KAR-C1ql1-Bai3 complex in the cerebellum.
摘要:
红藻氨酸(KA)型谷氨酸受体(KAR)通过其致离子和代谢作用与各种神经精神和神经系统疾病有关。然而,与AMPA和NMDA型受体功能相比,KAR生物学的许多方面仍未完全了解。我们的研究表明,KAR在小脑组织攀爬纤维(CF)-浦肯野细胞(PC)突触和突触可塑性中的重要作用,独立于它们的离子通道或代谢功能。GluK4KAR亚基的氨基末端结构域(ATD)与C1ql1结合,由CFs提供,并与Bai3相关,Bai3是在PC树突中表达的粘附型G蛋白偶联受体。缺乏GluK4的小鼠没有表现出KAR介导的反应,降低C1ql1和Bai3水平,更少的CF-PC突触,伴随着受损的长期抑郁和动眼学习。值得注意的是,GluK4的ATD的引入显著改善了所有这些表型。这些发现表明,KAR充当突触支架,通过在小脑中形成KAR-C1ql1-Bai3复合体来协调突触。