Early life seizures chronically disrupt L-type voltage gated calcium channel regulation of mGluR mediated long term depression via interactions with protein phosphatase 2A

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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 Ca V 1.2 and modulate its function; displacement of PP2A (C subunit, or PP2Ac) as well as PKA phosphorylation of Ca V 1.2 at serine 1928, result in enhanced Ca V 1.2 function. We found that ELS enhanced LTCC activity. We further found that pharmacological displacement of PP2Ac (but not PP2B/calcineurin) from Ca V 1.2 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 Ca 2+ 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. • The molecular mechanisms that result in increased mGluR-LTD after early life seizures (ELS) are due to • chronic hyperactive signaling via L-type calcium channels (LTCCs) • pharmacological dysregulation of the interaction of Ca V 1.2 and PP2a that normally regulates mGluR-LTD • LTCCs and internal calcium stores that interact in concert to regulate mGluR-LTD • PKA mediated phosphorylation that regulates mGluR-LTD

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