Regulation of the Ca²⁺ Channel Ca_V1.2 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 G_s-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca²⁺ channel (LTCC) Ca_V1.2. Phosphorylation of Ca_V1.2 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 Ca_V1.2. This work identifies Ca_V1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca²⁺ channel Ca_V1.2 on Ser¹⁹²⁸ is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser¹⁹²⁸ as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.