Abstract Supplement to Parent Grant Dysregulation of Cav1.2 by beta amyloid peptide L-type Ca2+ channels (LTCC) are key regulators of gene transcription, neuronal excitability, and synaptic functions. Cav1.2 is the prevalent LTCC in brain (Hell et al., 1993, JCB 123, 949-962). Chronically increased Ca2+ influx via LTCCs has been implicated early on in senile symptoms and Alzheimer’s disease (AD) (e.g., Science 272, 1017). We found that aged rats have significantly increased PKA-mediated phosphorylation of Cav1.2 on Serine 1928 (Davare and Hell, 2003, PNAS 100, 16018-23), which increases Cav1.2 channel activity (Qian, …, Hell, 2017, Sci Sig 10, eaaf9659). We also found that Cav1.2 forms a unique signaling complex with the b2 adrenergic receptor (b2 AR) (e.g., Davare et al., 2001, Science 293, 98), making Cav1.2 a prime target for b2 AR signaling. Oligomeric b amyloid peptide 1-42 (Abo) stimulates the b2 AR. Our supportive evidence indicates that Abo increase Cav1.2 activity via the b2 AR and the ensuing S1928 phosphorylation. Aim 1 is to test whether Cav1.2 dysregulation by Abo via Cav1.2-associated b2 AR occurs in dendrites and spines (Ca2+ imaging) and whether blocking this signaling alleviates Abo neurotoxicity. Aim 2 is to test whether Abo - b2 AR - S1928 signaling stimulates surface insertion of Ca2+ permeable (CP) AMPARs (GluA1 homomers) and blocking CP- AMPARs alleviates Abo neurotoxicity. Aim 3 will test the role of Abo - b2 AR - S1928 signaling in augmentation of long-term depression (LTD) by Abo, and in long-term potentiation, which is impaired by Abo. We recently proved that S1928 phosphorylation downstream of endogenous During our work on LTD we realized that in adult mice it can only readily be induced during evening and night hours, the active phase of mice. We then found that S1928 phosphorylation downstream of endogenous norepinephrine (NE) signaling is strictly required for LTD. For the Supplement we propose to test the emerging hypothesis that LTD in adult mice has a circadian rhythm that is driven by the established increase NE during active (night) phase and acts via b2 AR – S1928 signaling. The candidate Adejia Boutté will be central to execute the electrophysiology.