Impaired clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimer’s disease

ABSTRACTPatients 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 that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). 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.

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Dysregulated clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimer's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105454 ◽

2021 ◽

pp. 105454

Author(s):

Allison R. Fusilier ◽

Jennifer A. Davis ◽

Jodi R. Paul ◽

Stefani D. Yates ◽

Laura J. McMeekin ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Spatial Memory ◽

Clock Gene ◽

Inhibitory Transmission ◽

Clock Gene Expression ◽

Model Of Alzheimer’S Disease ◽

Diurnal Regulation

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Early derailment of firing properties in CA1 pyramidal cells of the ventral hippocampus in an Alzheimer's disease mouse model

Experimental Neurology ◽

10.1016/j.expneurol.2021.113969 ◽

2021 ◽

pp. 113969

Author(s):

Elena Spoleti ◽

Paraskevi Krashia ◽

Livia La Barbera ◽

Annalisa Nobili ◽

Carmen Alina Lupascu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Pyramidal Cells ◽

Ventral Hippocampus ◽

Ca1 Pyramidal Cells ◽

Firing Properties

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Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

Molecular Psychiatry ◽

10.1038/s41380-019-0483-4 ◽

2019 ◽

Vol 25 (12) ◽

pp. 3380-3398 ◽

Cited By ~ 15

Author(s):

Sara Hijazi ◽

Tim S. Heistek ◽

Philip Scheltens ◽

Ulf Neumann ◽

Derya R. Shimshek ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Neuronal Network ◽

Pyramidal Cells ◽

Network Activity ◽

Inhibitory Input ◽

Model Of Alzheimer’S Disease ◽

Entry Points ◽

Interneuron Activity

AbstractNeuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

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Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

eNeuro ◽

10.1523/eneuro.0059-18.2018 ◽

2018 ◽

Vol 5 (4) ◽

pp. ENEURO.0059-18.2018 ◽

Cited By ~ 5

Author(s):

Lingxuan Chen ◽

Takashi Saito ◽

Takaomi C. Saido ◽

Istvan Mody

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Pyramidal Cells ◽

Model Of Alzheimer’S Disease ◽

Quantitative Analyses

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Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade

10.1101/2021.03.29.437466 ◽

2021 ◽

Author(s):

Adrien Paumier ◽

Sylvie Boisseau ◽

Karin Pernet-Gallay ◽

Alain Buisson ◽

Mireille Albrieux

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Disease Progression ◽

Spatial Working Memory ◽

Specific Inhibitor ◽

Amyloid Β ◽

Neuronal Dysfunction ◽

Channel Activation ◽

Model Of Alzheimer’S Disease

AbstractBackgroundThe sequence of cellular dysfunctions in preclinical Alzheimer’s disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer’s disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of such accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimer’s disease progression.MethodsWe administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels.ResultsOur results revealed that the first observable disruptions in the Alzheimer’s disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model.ConclusionThe toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

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Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease

Experimental Neurology ◽

10.1016/j.expneurol.2012.05.011 ◽

2012 ◽

Vol 236 (2) ◽

pp. 249-258 ◽

Cited By ~ 51

Author(s):

Marilyn J. Duncan ◽

J. Tyler Smith ◽

Kathleen M. Franklin ◽

Tina L. Beckett ◽

M. Paul Murphy ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythms ◽

Clock Gene ◽

Clock Gene Expression ◽

Effects Of Aging

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Chemogenetic activation of midline thalamic nuclei fails to ameliorate memory deficits in two mouse models of Alzheimer's disease

10.1101/2021.06.30.450500 ◽

2021 ◽

Author(s):

Shivali Kohli ◽

Lilya Andrianova ◽

Gabriella Margetts-Smith ◽

Erica Brady ◽

Michael Thomas Craig

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Mouse Models ◽

Viral Vectors ◽

Spatial Working Memory ◽

Memory Deficits ◽

Brain Regions ◽

Pathological Changes ◽

Thalamic Nuclei

One of the main features of Alzheimer's disease is the progressive loss of memory, likely due to pathological changes within brain regions such as the hippocampus and entorhinal cortex. These structures are embedded within the Papez circuit, an interconnected set of brain regions that are essential for episodic memory. The anterior thalamic nuclei (ATN) and thalamic nucleus reuniens (NRe) are both extensively and reciprocally connected with these important memory regions, so we sought to test the hypothesis that chemogenetically-enhancing neurotransmission through NRe and ATN would ameliorate memory deficits in two mechanistically-distinct mouse models of Alzheimer's disease. Using the hAPP-J20 mouse model of amyloidopathy and the Tg4510 mouse model of tauopathy, we carried out stereotaxic injections of viral vectors to transduce hM3Dq (Gq)_mCherry into NRe or the anterio-dorsal/anterio-ventral nuclei of ATN, using mCherry as a control. At nine months (hAPP-J20) or six months (Tg4510) of age, mice underwent a behaviour battery of open field (OF), novel object recognition (NOR) and radial arm maze (RAM), with DREADD agonist 21 administered 30min prior to each behaviour test. Tissue was collected post-behaviour to confirm injection site and virus expression. Both Tg4510 and hAPP-J20 mice show marked hyperactivity in the OF, significant deficits in recognition memory, and a significant impairment in spatial reference and spatial working memory. Unexpectedly, chemogenetic activation of ATN or NRe did not significantly improve these memory impairments or reduce the observed hyperactivity. This may be due to compensation elsewhere within the memory circuit, or that the pathological changes are too far advanced for behaviour reversal.

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