Regulation of the Ca 2+ Channel Ca V 1.2 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 β AR and its downstream effectors, the trimeric stimulatory G -protein, adenylyl cyclase (AC), and the cAMP-dep...
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Veröffentlicht in: | The Journal of neuroscience 2023-07, Vol.43 (30), p.5559-5573 |
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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 β
AR and its downstream effectors, the trimeric stimulatory G
-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca
channel (LTCC) Ca
1.2. Phosphorylation of Ca
1.2 by PKA on Ser
is required for the upregulation of Ca
influx on β
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 Ser
phosphorylation
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 β
AR antagonists and peptides that displace β
AR from Ca
1.2. This work identifies Ca
1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.
We show that phosphorylation of the Ca
channel Ca
1.2 on Ser
is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser
as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory. |
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ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.1521-22.2023 |