Abstract
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 (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca(2+) channel (LTCC) Ca(V)1.2. Phosphorylation of Ca(V)1.2 by PKA on Ser(1928) is required for the upregulation of Ca(2+) influx on β(2) 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(1928) 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 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 We 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 long-term depression (LTD). Identification of Ser(1928) as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.