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Contributed by Richard L. Huganir, August 18, 2020 (sent for review July 15, 2020; reviewed by Lin Mei and Peter Penzes)
Significance
AMPA receptors (AMPARs) are the principle postsynaptic glutamate receptors mediating fast excitatory synaptic transmission in the brain. Regulation of synaptic AMPAR expression is required for the expression of synaptic plasticity and normal brain function. The turnover of AMPARs within synapses is highly dynamic, and the molecular mechanisms underlying AMPAR trafficking remain unclear. Here we report that GRIP1, an AMPAR-binding protein, plays an essential role in delivering AMPAR into synapses during synaptic plasticity, particularly in long-term potentiation. In addition, the deletion of Grip1 causes synaptic plasticity deficits and impaired learning and memory. Our study reveals a mechanism through which GRIP1 regulates AMPAR trafficking and impacts activity-dependent synaptic strengthening, as well as learning and memory.
Abstract
Hebbian plasticity is a key mechanism for higher brain functions, such as learning and memory. This form of synaptic plasticity primarily involves the regulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) abundance and properties, whereby AMPARs are inserted into synapses during long-term potentiation (LTP) or removed during long-term depression (LTD). The molecular mechanisms underlying AMPAR trafficking remain elusive, however. Here we show that glutamate receptor interacting protein 1 (GRIP1), an AMPAR-binding protein shown to regulate the trafficking and synaptic targeting of AMPARs, is required for LTP and learning and memory. GRIP1 is recruited into synapses during LTP, and deletion of Grip1 in neurons blocks synaptic AMPAR accumulation induced by glycine-mediated depolarization. In addition, Grip1 knockout mice exhibit impaired hippocampal LTP, as well as deficits in learning and memory. Mechanistically, we find that phosphorylation of serine-880 of the GluA2 AMPAR subunit (GluA2-S880) is decreased while phosphorylation of tyrosine-876 on GluA2 (GluA2-Y876) is elevated during chemically induced LTP. This enhances the strength of the GRIP1–AMPAR association and, subsequently, the insertion of AMPARs into the postsynaptic membrane. Together, these results demonstrate an essential role of GRIP1 in regulating AMPAR trafficking during synaptic plasticity and learning and memory.
Footnotes
↵1H.L.T., S.-L.C., and Q.Z. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: rhuganir{at}jhmi.edu.
Author contributions: H.L.T., S.-L.C., and R.L.H. designed research; H.L.T., S.-L.C., and Q.Z. performed research; H.L.T., S.-L.C., and Q.Z. analyzed data; and H.L.T. wrote the paper.
Reviewers: L.M., Case Western Reserve University; and P.P., Northwestern University.
The authors declare no competing interest.
Data Availability.
All study data are included in the paper.
Published under the PNAS license.
References
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GRIP1 regulates synaptic plasticity and learning and memory
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