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Activity-dependent trafficking of AMPA receptors (AMPARs) and subsequent long-term synaptic strengthening underlie different forms of learning and memory. The AMPAR subunit GluA1 amino-terminal domain (ATD, a. k. a. NTD) plays a critical role in synaptic AMPAR trafficking and LTP. The GluA1 ATD accounts for almost half the proteins' size and protrudes significantly into the synaptic cleft, hence it is ideally localized for interactions with synaptic cleft proteins. Using unbiased proteomics, we identified the epilepsy and intellectual disability-associated voltage-gated calcium channel (VGCC) auxiliary subunit α2δ-1 as a GluA1 ATD-interacting protein. At CA1 synapses, postsynaptic deletion of α2δ-1 selectively enhanced basal synaptic AMPAR, but not NMDAR currents. Conversely, presynaptic α2δ-1 deletion did not affect basal synaptic transmission but decreased LTP. α2δ-1 deletion in hippocampal field CA3 impaired performance in an object location memory task, but not other forms of memory. Collectively, our work identifies α2δ-1 as an extracellular AMPAR regulatory protein with distinct pre- and postsynaptic functions: in cis, limiting AMPAR access to synapses; in trans, facilitating LTP. Furthermore, it expands our understanding of the mechanisms underlying α2δ-1's regulation of hippocampal function and raise the possibility that α2δ-1-dependent AMPAR regulation may contribute to the effects of gabapentinoid drugs.