UC Davis

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.