He Chun-Wei, Díaz Elva
Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States.
Front Pharmacol. 2025 May 21;16:1568908. doi: 10.3389/fphar.2025.1568908. eCollection 2025.
The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synaptic plasticity as well as hippocampal-dependent learning and memory. Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression. These findings suggest that SynDIG4 may play an important role in regulating AMPAR distribution through intracellular trafficking mechanisms; however, the precise roles by which SynDIG4 governs AMPAR distribution remain unclear. Here, we characterized the endocytosis and recycling of GluA1-containing AMPARs under basal conditions. We did not observe any change in baseline endocytosis; however, we did observe a significant decrease in recycling of GluA1-containing AMPARs in cultured hippocampal neurons from mice lacking SynDIG4. This resulted in a significant increase in the levels of internal GluA1 and GluA2, along with greater colocalization of these subunits with Rab4-positive recycling endosomes. Notably, the overlap between Rab4-positive and Rab11-positive vesicles was elevated in hippocampal neurons lacking SynDIG4, suggesting an impairment in the trafficking between these compartments. Furthermore, our findings revealed a reduction in surface GluA1 within synaptic regions of hippocampal neurons lacking SynDIG4. Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions. This regulatory function of SynDIG4 may contribute to the deficits in GluA1-dependent synaptic plasticity and impairment of hippocampal-dependent behaviors observed in SynDIG4 deficient mice.
跨膜蛋白突触分化诱导基因4（SynDIG4）作为α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）的辅助因子，在兴奋性突触可塑性以及海马依赖性学习和记忆中起关键作用。缺乏SynDIG4的小鼠GluA1和GluA2的表面表达减少，并且在单次强直刺激诱导的长时程增强和N-甲基-D-天冬氨酸受体（NMDAR）依赖性长时程抑制中受损。这些发现表明，SynDIG4可能通过细胞内运输机制在调节AMPAR分布中起重要作用；然而，SynDIG4控制AMPAR分布的确切作用仍不清楚。在这里，我们表征了基础条件下含GluA1的AMPAR的内吞作用和再循环。我们没有观察到基线内吞作用有任何变化；然而，我们确实观察到来自缺乏SynDIG4的小鼠的培养海马神经元中含GluA1的AMPAR再循环有显著减少。这导致细胞内GluA1和GluA2水平显著增加，以及这些亚基与Rab4阳性再循环内体的共定位增加。值得注意的是，缺乏SynDIG4的海马神经元中Rab4阳性和Rab11阳性囊泡之间的重叠增加，表明这些区室之间的运输受损。此外，我们的发现揭示了缺乏SynDIG4的海马神经元突触区域内表面GluA1减少。总的来说，这些结果表明，SynDIG4通过Rab4依赖性内体再循环途径调节含GluA1的AMPAR的分布，从而在基线条件下维持突触区域的AMPAR水平。SynDIG4的这种调节功能可能导致在缺乏SynDIG4的小鼠中观察到的GluA1依赖性突触可塑性缺陷和海马依赖性行为受损。
