Leana-Sandoval Gerardo, Kolli Ananth V, Sandoval Matthew A, Saavedra Emily, Li Kathy H, Chen Lulu Y, Burlingame Alma L, Ramírez-Franco Jorge, Díaz-Alonso Javier
Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA.
Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA.
bioRxiv. 2024 Dec 2:2024.12.02.626379. doi: 10.1101/2024.12.02.626379.
Activity-dependent synaptic accumulation of AMPA receptors (AMPARs) and subsequent long-term synaptic strengthening underlie different forms of learning and memory. The AMPAR subunit GluA1 amino-terminal domain is essential for synaptic docking of AMPAR during LTP, but the precise mechanisms involved are not fully understood. Using unbiased proteomics, we identified the epilepsy and intellectual disability-associated VGCC auxiliary subunit α2δ1 as a candidate extracellular AMPAR slot. Presynaptic α2δ1 deletion in CA3 affects synaptic AMPAR incorporation during long-term potentiation, but not basal synaptic transmission, at CA1 synapses. Consistently, mice lacking α2δ1 in CA3 display a specific impairment in CA1-dependent spatial memory, but not in memory tests involving other cortical regions. Decreased seizure susceptibility in mice lacking α2δ1 in CA3 suggests a regulation of circuit excitability by α2δ1/AMPAR interactions. Our study sheds light on the regulation of activity-dependent AMPAR trafficking, and highlights the synaptic organizing roles of α2δ1.
AMPA受体（AMPARs）的活性依赖性突触积累以及随后的长期突触增强是不同形式学习和记忆的基础。AMPAR亚基GluA1氨基末端结构域对于LTP期间AMPAR的突触对接至关重要，但其中涉及的精确机制尚未完全了解。通过非偏向蛋白质组学，我们鉴定出与癫痫和智力残疾相关的电压门控钙通道辅助亚基α2δ1作为细胞外AMPAR插槽的候选者。CA3区突触前α2δ1缺失会影响长期增强过程中CA1突触处的突触AMPAR整合，但不影响基础突触传递。同样，CA3区缺乏α2δ1的小鼠在依赖CA1的空间记忆方面表现出特定损伤，但在涉及其他皮质区域的记忆测试中没有。CA3区缺乏α2δ1的小鼠癫痫易感性降低，这表明α2δ1/AMPAR相互作用对回路兴奋性有调节作用。我们的研究揭示了活性依赖性AMPAR转运的调节机制，并突出了α2δ1的突触组织作用。
