Intracellular Ca ²⁺ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease

Significance Although both patients with Alzheimer’s disease (AD) and mouse models of the disease suffer from a profound neuronal hyperactivity mediating an impairment of memory and cognition, the underlying mechanisms remain elusive. Here, we show that neuronal hyperactivity is a hallmark of healthy aging but is further aggravated by AD-related mutations in presenilin 1 protein. AD-mediated enhancement of neuronal hyperactivity occurred even in the absence of amyloid plaques and neuroinflammation, mainly due to a presenilin-mediated dysfunction of intracellular Ca 2+ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors. Emptying the stores normalized neuronal network activity in mutant mice, thus identifying presynaptic Ca 2+ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments.