Premium
The &[Alpha]2δ‐1–NMDA Receptor Coupling is Essential for Corticostriatal Long‐Term Potentiation and is Involved in Learning and Memory
Author(s) -
ZHOU JINGJING,
Li DePei,
Chen ShaoRui,
Luo Yi,
Pan HuiLin
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.738.2
Subject(s) - long term potentiation , neuroscience , nmda receptor , synaptic plasticity , long term depression , medium spiny neuron , striatum , chemistry , glutamate receptor , biology , ampa receptor , receptor , dopamine , biochemistry
The striatum receives extensive cortical input and plays a prominent role in motor learning and habit formation. Glutamate N‐methyl‐Daspartate (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 crosstalk 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 may adversely affect cognitive function by targeting α2δ‐1–NMDAR complexes. Support or Funding Information Human brain tissues were obtained from the Harvard Brain Tissue Resources Center, a NeuroBioBank Repository funded by the National Institutes of Health. This work was supported by the National Institutes of Health (GM120844 and NS101880 to H.‐L.P.) and by the N.G. and Helen T. Hawkins Endowment. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .