The α2δ-1-NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory
In: The Journal of biological chemistry, Jg. 293 (2018-05-15), Heft 50
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Zugriff:
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 α2δ-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 α2δ-1 trafficking with gabapentin or disrupting the α2δ-1-NMDAR interaction with an α2δ-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 α2δ-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 α2δ-1 and NMDARs is of high physiological relevance and that a TBS-induced switch from α2δ-1-free to α2δ-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 α2δ-1-NMDAR complexes.
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The α2δ-1-NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory
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Autor/in / Beteiligte Person: | De Pei Li ; Hui Lin Pan ; Jing Jing Zhou ; Luo, Yi ; Shao Rui Chen |
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Zeitschrift: | The Journal of biological chemistry, Jg. 293 (2018-05-15), Heft 50 |
Veröffentlichung: | 2018 |
Medientyp: | unknown |
ISSN: | 1083-351X (print) |
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