Neurobiol Dis. 2025 Mar 25:106884. doi: 10.1016/j.nbd.2025.106884. Online ahead of print.
ABSTRACT
We probed the dependence of metabotropic glutamate receptor dependent long-term depression (mGluR-LTD) on L-type voltage gated calcium channels (LTCCs). In prior work, we found that in a rat model of early life seizures (ELS), exaggerated mGluR-LTD was partly mediated by LTCCs and protein phosphatase 2A (PP2A). Here, we further investigated the interactive role of LTCCs, PP2A, and protein kinase A (PKA) in this same model. PP2Ac is known to bind CaV1.2 and modulate its function; displacement of PP2A (C subunit, or PP2Ac) as well as PKA phosphorylation of CaV1.2 at serine 1928, result in enhanced CaV1.2 function. We found that ELS enhanced LTCC activity. We further found that pharmacological displacement of PP2Ac (but not PP2B/calcineurin) from CaV1.2 enhanced mGluR-LTD in controls. This was occluded by blockade of PP2A or ELS. The LTCC-dihydropyridine agonist BayK 8644 enhanced mGluR-LTD in controls, which was also occluded by ELS. Up-regulation of both intracellular Ca2+ and PKA activity were implicated in ELS enhancement of mGluR-LTD, as LTD was normalized in ELS by depletion of internal calcium stores or blockade of PKA. These results support a dynamic model of mGluR-LTD regulation by LTCCs through PP2Ac binding and phosphorylation by PKA. This regulation is chronically lost after ELS. Together with our prior work, these studies tie hyperactive LTCCs to the chronic ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.
PMID:40147739 | DOI:10.1016/j.nbd.2025.106884
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