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Intracellular Ca2+ 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 Ca2+ 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 Ca2+ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments. Neuronal hyperactivity is the emerging functional hallmark of Alzheimer’s disease (AD) in both humans and different mouse models, mediating an impairment of memory and cognition. The mechanisms underlying neuronal hyperactivity remain, however, elusive. In vivo Ca2+ imaging of somatic, dendritic, and axonal activity patterns of cortical neurons revealed that both healthy aging and AD-related mutations augment neuronal hyperactivity. The AD-related enhancement occurred even without amyloid deposition and neuroinflammation, mainly due to presenilin-mediated dysfunction of intracellular Ca2+ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors. In mutant but not wild-type mice, store emptying reduced both the frequency and amplitude of presynaptic Ca2+ transients and, most importantly, normalized neuronal network activity. Postsynaptically, the store dysfunction was minor and largely restricted to hyperactive cells. These findings identify presynaptic Ca2+ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments.