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

Abstract

Summary 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.

Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease

“…The binding of Aβ1-42 to CaMKII-positive synapses might explain why excitatory neurons, in particular, are affected. The increased frequencies and amplitudes of calcium oscillations that we observed with neprilysin inhibition as a means to elevate endogenous Aβ are consistent with results from Abramov et al (2009), showing increased release probability with thiorphan treatment in cultured hippocampal neurons. However, since neprilysin also degrades various enkephalins and peptide neurotransmitters, such as substance P, which can influence calcium stores (Heath et al, 1994), we additionally showed a lack of effect on calcium oscillations with neprilysin inhibition in APP KO neurons.…”

“…Interestingly, we observed that the mean firing rates were similar between TTX, vehicle and bicuculline treated WT neurons after 48 h consistent with findings suggesting that while single unit firing is unstable, networks maintain surprisingly stable firing frequencies ( Slomowitz et al, 2015 ). Aβ and APP have been implicated in normal HSP ( Gilbert et al, 2016 ; Galanis et al, 2021 ), and APP/PS1 mice were recently shown to have defective downscaling during sleep ( Zarhin et al, 2022 ). Defective HSP could help explain why AD transgenic mice are more susceptible to pharmacologically-induced and spontaneous seizures ( Minkeviciene et al, 2009 ; Reyes-Marin and Nuñez, 2017 ) and could provide a framework for explaining the increased sensitivity to seizures in AD patients ( Pandis and Scarmeas, 2012 ).…”

“…Further, prior in vivo work in AD transgenic mice has suggested that HSP mechanisms might be impaired, since chronic hypo- or hyper-activity via either long term sleep deprivation or induction, or unilateral whisker removal, conditions in which HSP should be engaged, negatively impacted AD transgenic compared to wild-type (WT) mice ( Kang et al, 2009 ; Tampellini et al, 2010 ). Recently, firing rate homeostasis was shown to be defective in APP/PS1 mice during sleep ( Zarhin et al, 2022 ).…”

A Comparison of Brain-State Dynamics across Common Anesthetic Agents in Male Sprague-Dawley Rats

“…Our data show that surgical-plane levels of PTB, ISO, and PRO all provide effective models to probe the mechanistic complexities of the coma-like brain state of burst suppression, such as cortical hyperexcitability [ 4 ], neurovascular coupling [ 37 ], and local cortical spatiotemporal dynamics [ 38 ]. Indeed, ISO was recently shown to exhibit the same dysregulation in homeostatic neural-firing rates as nREM in pre-symptomatic mouse models of familial Alzheimer’s disease [ 39 ], indicating that ISO may serve as a useful model to explore the connection between the subclinical epileptiform activity and network hyperexcitability that is observed in some models of Alzheimer’s disease [ 40 , 41 ].…”

Circuit-specific selective vulnerability in the DMN persists in the face of widespread amyloid burden

“…In the APP/PS1 mouse, Aβ has been shown to increase neuronal activity (Busche et al, 2008; 2012) as well as decrease neuron firing, perhaps explained by a neuron’s proximity to nearby plaques (Klee et al, 2020). This may also depend on brain state or context (Zarhin et al, 2022), highlighting the need to examine neuronal activity in multiple regions across a range of naturally occurring conditions. At a lower spatial resolution, APP overexpression reduces the power of gamma oscillations (Palop and Mucke, 2016) and alters coupling between the hippocampus and cortex during sleep (Zhurakovskaya et al, 2019).…”