The VGCC auxiliary subunit α2δ1 is an extracellular GluA1 interactor and regulates LTP, spatial memory, and seizure susceptibility.

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.