The 2-1–NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory

The striatum receives extensive cortical input and plays a prominent role in motor learning and habit formation. Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated long-term potentiation (LTP) is a major synaptic plasticity involved in learning and memory. However, the molecular mechanism underlying NMDAR plasticity in corticostriatal LTP is unclear. Here, we show that theta-burst stimulation (TBS) consistently induced corticostriatal LTP and increased the coincident presynaptic and postsynaptic NMDAR activity of medium spiny neurons. We also found that 2-1 (previously known as a subunit of voltage-gated calcium channels; encoded by the Cacna2d1 gene) physically interacted with NMDARs in the striatum of mice and humans, indicating that this cross-talk is conserved across species. Strikingly, inhibiting 2-1 trafficking with gabapentin or disrupting the 2-1–NMDAR interaction with an 2-1 C terminus–interfering peptide abolished TBS-induced LTP. In Cacna2d1-knockout mice, TBS failed to induce corticostriatal LTP and the associated increases in presynaptic and postsynaptic NMDAR activities. Moreover, systemic gabapentin treatment, microinjection of 2-1 C terminus–interfering peptide into the dorsomedial striatum, or Cacna2d1 ablation impaired the alternation T-maze task and rotarod performance in mice. Our findings indicate that the interaction between 2-1 and NMDARs is of high physiological relevance and that a TBS-induced switch from 2-1–free to 2-1– bound NMDARs is critically involved in corticostriatal LTP and LTP-associated learning and memory. Gabapentinoids at high doses may adversely affect cognitive function by targeting 2-1–NMDAR complexes.