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Network abnormalities and interneuron dysfunction in Alzheimer’s disease
Author(s) -
Palop Jorge J.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040396
Subject(s) - interneuron , neuroscience , inhibitory postsynaptic potential , biology , parvalbumin , nerve net , biological neural network , rhythm , psychology , medicine
Abstract Background Alzheimer’s disease (AD) results in deterioration of cognitive functions and abnormal patterns of neuronal network activity, including network hyperactivity and altered oscillatory rhythms, but the underlying cellular and circuit mechanisms are poorly understood. Methods The brain relies on oscillatory rhythms, generated by inhibitory interneurons, to precisely time neuronal firing required for circuit functions. Results In this session, we will discuss our recent findings suggesting that interneuron impairment critically contributes to network hyperactivity, altered oscillatory rhythms and cognitive decline in multiple mouse models of AD. We found that oscillatory rhythms reflect behavioural states and strongly modulate network hypersynchrony in mouse models of AD, including including J20 and APP/PS1 mice. Specifically, pathological network hypersynchrony emerges during resting states characterized by decreased gamma oscillatory power and aberrant increases of low‐frequency (12‐20 Hz) oscillatory power. Inhibitory interneuron deficits in AD mouse models are in part mediated by decreased levels of the interneuron‐predominant voltage‐gated sodium channel Nav1.1 subunit. Importantly, restoring Nav1.1 levels and interneuron function by Nav1.1 BAC overexpression or interneuron transplants improves interneuron–dependent gamma oscillatory activity, theta‐gamma phase‐amplitude coupling, survival, circadian rhythms and cognitive performance in J20 and APP/PS1 mice, revealing key functional roles for Nav1.1 and inhibitory interneurons. We will also discuss the specific contributions of interneuron cell types such as fast‐spiking (FS, PV) and non‐fast spiking (NFS, SOM) interneurons to generate gamma oscillatory activity and the underlying circuits and cellular mechanisms responsible for altered gamma oscillations in AD mice by optogenetic approaches and multi‐unit and local field potential (LFP) recordings in vivo . Our results suggest that distinct interneurons cell types such as PV and SOM interneurons synergistically cooperate to generate gamma oscillation in vivo and that J20 mice have cell‐type specific functional impairments in this circuit that lead to impaired oscillatory activity. Finally, we will also discuss our translational efforts identifying small molecule Nav1.1 enhancers to increase interneuron function. Conclusion Our results highlight the potential therapeutic benefit of restoring inhibitory interneuron function and oscillatory rhythms for cognitive functions and that targeting network dysfunction represents an attractive and complementary therapeutic approach.