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Article Abstract
GABA-A receptors (GABARs) are crucial for development and function of the brain. Altered GABAergic transmission is hypothesized to be involved in neurodevelopmental disorders. Recently, we identified Shisa7 as a GABAR auxiliary subunit that modulates GABAR trafficking and GABAergic transmission. However, the underlying molecular mechanisms remain elusive. Here we generated a knock-in (KI) mouse line that is phospho-deficient at a phosphorylation site in Shisa7 (S405) and combined with electrophysiology, imaging and behavioral assays to illustrate the role of this site in GABAergic transmission and plasticity as well as behaviors. We found that expression of phospho-deficient mutants diminished α2-GABAR trafficking in heterologous cells. Additionally, α1/α2/α5-GABAR surface expression and GABAergic inhibition were decreased in hippocampal neurons in KI mice. Moreover, chemically induced inhibitory long-term potentiation was abolished in KI mice. Lastly, KI mice exhibited hyperactivity, increased grooming and impaired sleep homeostasis. Collectively, our study reveals a phosphorylation site critical for Shisa7-dependent GABARs trafficking which contributes to behavioral endophenotypes displayed in neurodevelopmental disorders.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9556544 | PMC |
| http://dx.doi.org/10.1038/s41386-022-01334-0 | DOI Listing |
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