Intracellular calcium stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease

TitleIntracellular calcium stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease
Publication TypeJournal Article
Year of Publication2018
AuthorsC, Lerdkrai, N Asavapanumas, B Brawek, Y Kovalchuk, N Mojtahedi, M Olmedillas-del-Moral, and O Garaschuk
JournalPNAS USA
Date Published01/2018
Type of Articlejournal article
Abstract

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.

URLhttp://www.pnas.org/content/early/2018/01/18/1714409115.full.pdf