Dysregulated clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in amyloid precursor protein transgenic mice

Abstract

Patients with Alzheimer’s disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock) in Tg-SwDI mice with human amyloid-beta precursor protein mutations. Here, we report that Tg-SwDI mice failed to show day/night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer’s disease symptoms or delay pathological onset.

Simultaneous Alteration of the Circadian Variation of Memory, Hippocampal Synaptic Plasticity, and Metabolism in a Triple Transgenic Mouse Model of Alzheimer’s Disease

“…Moreover, our data indicate a simultaneous loss of circadian variation of key properties of synaptic mitochondria in early AD, together with a similar loss of the circadian variation of memory performance and LTP magnitude in 3xTg mice. This provides the first demonstration in the 3xTg mouse model of AD, which shows circadian phenotypes more consistent with human AD ( Sheehan and Musiek, 2020 ), of circadian variations of memory and synaptic plasticity that were shown in other AD rodent models ( Baño Otalora et al, 2012 ; Duncan et al, 2012 ; Lanté et al, 2015 ; Stevanovic et al, 2017 ; Petrasek et al, 2018 ; He et al, 2020 ; Fusilier et al, 2021 ) and in Drosophila AD models ( Chen et al, 2014 ; Long et al, 2014 ) and only inferred from proteomic analysis in 3xTg-AD mice ( Bellanti et al, 2017 ).…”

The clock modulator Nobiletin mitigates astrogliosis‐associated neuroinflammation and disease hallmarks in an Alzheimer’s disease model

“…[15][16][17][18][19] Multiple lines of evidence also directly link circadian clocks with AD. 10,11,20 An intact circadian oscillator, containing positive (CLOCK, BMAL1, RORs) and negative (PERs, CRYs, REV-ERBs) core clock components, 21 is required for neuronal maintenance and function, cognitive functions, and behavior. 22 Importantly, circadian disruption by genetic mutations or environmental factors leads to neurodegeneration and impaired cognitive functions.…”

Examination of diurnal variation and sex differences in hippocampal neurophysiology and spatial memory

“…Previous work from our laboratory revealed that sIPSCs onto CA1 pyramidal neurons exhibit diurnal differences and that those diurnal differences are lost in a mouse model of Alzheimer’s Disease (Fusilier et al ., 2021). Here, we replicated and expanded on previous findings by examining sIPSCs in both sexes and conducting additional experiments in the presence of TTX (mIPSCs) to begin to identify pre- and post-synaptic mechanisms contributing to diurnal differences.…”

“…A previous study in rats found that membrane excitability oscillated across circadian time, with neurons being more depolarized during the subjective late night/subjective early day (Naseri Kouzehgarani et al ., 2020). We recently reported increased nighttime excitability in mouse CA1 pyramidal neuron excitability (Fusilier et al ., 2021). Here, we replicated our previous findings and expanded our study to account for potential sex differences and the influence of the anterior-posterior hippocampal axis.…”