Table_1_Tyro3 promotes the maturation of glutamatergic synapses.docx

The receptor tyrosine kinase Tyro3 is abundantly expressed in neurons of the neocortex, hippocampus, and striatum, but its role in these cells is unknown. We found that neuronal expression of this receptor was markedly up-regulated in the postnatal mouse neocortex immediately prior to the final development of glutamatergic synapses. In the absence of Tyro3, cortical and hippocampal synapses never completed end-stage differentiation and remained electrophysiologically and ultrastructurally immature. Tyro3−/− cortical neurons also exhibited diminished plasma membrane expression of the GluA2 subunits of AMPA-type glutamate receptors, which are essential to mature synaptic function. Correspondingly, GluA2 membrane insertion in wild-type neurons was stimulated by Gas6, a Tyro3 ligand widely expressed in the postnatal brain. Behaviorally, Tyro3−/− mice displayed learning enhancements in spatial recognition and fear-conditioning assays. Together, these results demonstrate that Tyro3 promotes the functional maturation of glutamatergic synapses by driving plasma membrane translocation of GluA2 AMPA receptor subunits.

酪氨酸激酶受体Tyro3在皮层、海马体和纹状体的神经元中表达丰富，但其在此类细胞中的功能尚不明确。本研究发现，该受体的神经元表达在新生小鼠皮层发育的最后阶段，即在谷氨酸能突触最终形成之前显著上调。在Tyro3缺失的情况下，皮层和海马体突触无法完成终末分化，并在电生理学和超微结构上保持不成熟状态。Tyro3−/−皮层神经元还表现出AMPA型谷氨酸受体GluA2亚基在质膜上的表达减少，而这些亚基对于成熟突触功能至关重要。相应地，野生型神经元中GluA2亚基的膜插入由Gas6（一种在新生脑中广泛表达的Tyro3配体）刺激。在行为学方面，Tyro3−/−小鼠在空间识别和恐惧条件化测试中表现出学习能力的增强。综上所述，Tyro3通过驱动GluA2 AMPA受体亚基的质膜转位，促进谷氨酸能突触的功能成熟。