Miao Sheng, Fourgeaud Lawrence, Burrola Patrick G, Stern Shani, Zhang Yuhan, Happonen Kaisa E, Novak Sammy Weiser, Gage Fred H, Lemke Greg
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, United States.
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States.
Front Neurosci. 2024 Feb 12;18:1327423. doi: 10.3389/fnins.2024.1327423. eCollection 2024.
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. 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, 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.
受体酪氨酸激酶Tyro3在新皮层、海马体和纹状体的神经元中大量表达，但其在这些细胞中的作用尚不清楚。我们发现，在谷氨酸能突触最终发育之前，该受体在出生后小鼠新皮层中的神经元表达显著上调。在没有Tyro3的情况下，皮层和海马体突触从未完成终末期分化，在电生理和超微结构上仍不成熟。皮层神经元还表现出AMPA型谷氨酸受体的GluA2亚基在质膜上的表达减少，而这些亚基对成熟的突触功能至关重要。相应地，野生型神经元中GluA2的膜插入受到Gas6的刺激，Gas6是一种在出生后大脑中广泛表达的Tyro3配体。在行为上，小鼠在空间识别和恐惧条件测试中表现出学习能力增强。这些结果共同表明，Tyro3通过驱动GluA2 AMPA受体亚基的质膜易位促进谷氨酸能突触的功能成熟。
