| First Author | Zhou JJ | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 50 | Pages | 19354-19364 |
| PubMed ID | 30355732 | Mgi Jnum | J:272874 |
| Mgi Id | MGI:6268603 | Doi | 10.1074/jbc.RA118.003977 |
| Citation | Zhou JJ, et al. (2018) The alpha2delta-1-NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory. J Biol Chem 293(50):19354-19364 |
| abstractText | 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 alpha2delta-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 alpha2delta-1 trafficking with gabapentin or disrupting the alpha2delta-1-NMDAR interaction with an alpha2delta-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 alpha2delta-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 alpha2delta-1 and NMDARs is of high physiological relevance and that a TBS-induced switch from alpha2delta-1-free to alpha2delta-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 alpha2delta-1-NMDAR complexes. |
