Regulation of the Ca2+ Channel CaV1.2 Supports Spatial Memory and Its Flexibility and LTD

Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The β2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-de...

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Veröffentlicht in:The Journal of neuroscience 2023-07, Vol.43 (30), p.5559-5573
Hauptverfasser: Ireton, Kyle E, Xing, Xiaoming, Kim, Karam, Weiner, Justin C, Jacobi, Ariel A, Grover, Aarushi, Foote, Molly, Ota, Yusuke, Berman, Robert, Hanks, Timothy, Hell, Johannes W
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Sprache:eng
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Zusammenfassung:Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The β2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca2+ channel (LTCC) CaV1.2. Phosphorylation of CaV1.2 by PKA on Ser1928 is required for the upregulation of Ca2+ influx on β2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by β2 AR antagonists and peptides that displace β2 AR from CaV1.2. This work identifies CaV1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1521-22.2023