Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Daniel Zarhin, Refaela Atsmon, Antonella Ruggiero, Halit Baeloha, Shiri Shoob, Oded Scharf, Leore R. Heim, Nadav Buchbinder, Ortal Shinikamin, Ilana Shapira, Boaz Styr, Gabriella Braun, Michal Harel, Anton Sheinin, Nitzan Geva, Yaniv Sela, Takashi Saito, Takaomi Saido, Tamar Geiger, Yuval NirYaniv Ziv, Inna Slutsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Original languageEnglish
Article number110268
JournalCell Reports
Volume38
Issue number3
DOIs
StatePublished - 18 Jan 2022

Funding

FundersFunder number
BIRAX Regenerative Medicine Initiative1849/17, 46BX18TKIS
MILLENNIA51/11, ERC-2019-CoG 864353, JPMJMS2024, 1326/15
Ministry of Science and Culture of Lower SaxonyZN3458
Sheila and Denis Cohen Charitable Trust
Horizon 2020 Framework Programme864353, 724866
European Research Council
Rosetrees TrustA2590
Deutsche Forschungsgemeinschaft448865644, 440813539
Volkswagen Foundation
Ministry of Science, Technology and Space
Japan Science and Technology Agency
Israel Science Foundation1663/18
Azrieli Foundation
Sackler Faculty of Medicine, Tel-Aviv University
Sagol School of Neuroscience, Tel Aviv University

    Keywords

    • Alzheimer's disease
    • DHODH
    • NREM
    • calcium imaging
    • firing rate homeostasis
    • general anesthesia
    • hippocampus
    • hyperexcitability
    • single-unit recordings
    • sleep

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