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Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease.

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.

SUBMITTER: Lerdkrai C

PROVIDER: S-EPMC5819404 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Intracellular Ca<sup>2+</sup> stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease.

Lerdkrai Chommanad C Asavapanumas Nithi N Brawek Bianca B Kovalchuk Yury Y Mojtahedi Nima N Olmedillas Del Moral Maria M Garaschuk Olga O

Proceedings of the National Academy of Sciences of the United States of America 20180122 6

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 Ca<sup>2+</sup> 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 amy ...[more]

PMID: 29358403

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Project description:BackgroundNeuronal hyperexcitability and inhibitory interneuron dysfunction are frequently observed in preclinical animal models of Alzheimer's disease (AD). This study investigates whether these microscale abnormalities explain characteristic large-scale magnetoencephalography (MEG) activity in human early-stage AD patients.MethodsTo simulate spontaneous electrophysiological activity, we used a whole-brain computational network model comprised of 78 neural masses coupled according to human structural brain topology. We modified relevant model parameters to simulate six literature-based cellular scenarios of AD and compare them to one healthy and six contrast (non-AD-like) scenarios. The parameters include excitability, postsynaptic potentials, and coupling strength of excitatory and inhibitory neuronal populations. Whole-brain spike density and spectral power analyses of the simulated data reveal mechanisms of neuronal hyperactivity that lead to oscillatory changes similar to those observed in MEG data of 18 human prodromal AD patients compared to 18 age-matched subjects with subjective cognitive decline.ResultsAll but one of the AD-like scenarios showed higher spike density levels, and all but one of these scenarios had a lower peak frequency, higher spectral power in slower (theta, 4-8Hz) frequencies, and greater total power. Non-AD-like scenarios showed opposite patterns mainly, including reduced spike density and faster oscillatory activity. Human AD patients showed oscillatory slowing (i.e., higher relative power in the theta band mainly), a trend for lower peak frequency and higher total power compared to controls. Combining model and human data, the findings indicate that neuronal hyperactivity can lead to oscillatory slowing, likely due to hyperexcitation (by hyperexcitability of pyramidal neurons or greater long-range excitatory coupling) and/or disinhibition (by reduced excitability of inhibitory interneurons or weaker local inhibitory coupling strength) in early AD.ConclusionsUsing a computational brain network model, we link findings from different scales and models and support the hypothesis of early-stage neuronal hyperactivity underlying E/I imbalance and whole-brain network dysfunction in prodromal AD.

Dataset Information

Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease.

Publications

Intracellular Ca<sup>2+</sup> stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease.

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