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 2 AR and its downstream effectors, the trimeric stimulatory G s protein, adenylyl cyclase, and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca 2+ channel Ca V 1.2. Phosphorylation of Ca V 1.2 by PKA on Ser 1928 is required for the upregulation of Ca 2+ influx upon β 2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1s-long 100 Hz tetani. However, the function of Ser 1928 phosphorylation in vivo is unknown. Here we show that S1928A knock-in 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, LTD has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by β 2 AR antagonists and peptides that displace β 2 AR from Ca V 1.2. This work identifies Ca V 1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD. Significance Statement Ireton et al. show that phosphorylation of the Ca 2+ channel Ca V 1.2 on Ser 1928 is important for consolidation of spatial memory and especially its reversal, and LTD. Identification of Ser1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.