Partial Suppression of Ca <sub>v</sub>2.1 Function Prevents Synaptic and Behavioral Impairments in Alzheimer's Disease Models

Abstract

Amyloid-β (Aβ)-dependent dysfunction and eventual loss of glutamatergic synapses is central to Alzheimer’s disease (AD) pathogenesis. However, the underlying mechanisms remain poorly understood, hindering the development of effective therapeutics. Here, we report that pathogenic Aβ causes a rapid, sustained enhancement of evoked glutamate release probability due to a specific functional potentiation of presynaptic Cav2.1 voltage-gated Ca2+ channels. Mechanistically, this is dependent on a signaling pathway initiated by membrane insertion of the Na+ leak channel ENaC at presynaptic terminals. Pharmacological Cav2.1 inhibition normalizes neurotransmitter release, thereby rescuing amyloid-β-induced loss of dendritic spines and synaptic long-term potentiation (LTP). Likewise, genetic Cav2.1 haploinsufficiency robustly prevents spine loss, memory deficits and premature mortality in AD model mice. Our findings reveal a previously unknown disease mechanism wherein enhanced neurotransmitter release drives AD pathogenesis, and suggest that partial suppression of Cav2.1 function can delay or prevent disease progression.