Interneuron circadian rhythms and tau-dependent network excitability in Alzheimer's disease pathogenesis

ABSTRACT Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting more than 6 million Americans. As AD only continues to increase in prevalence, new therapeutic approaches are needed to combat this disease. A combination of clinical, neuroimaging, and neurophysiological studies have provided converging evidence that network hyperexcitability, including mostly subclinical epileptiform activity, is an important aspect of the early stages of AD. Many AD models exhibit similar network hyperexcitability that is dependent on both APP/Aβ and tau. Because network hyperexcitability can potentially be targeted by a variety of treatment approaches, a better understanding of the underlying mechanisms is needed. Circadian variation is a prominent aspect of AD-related network hyperexcitability, which occurs mainly during the inactive phase in both AD patients and mouse models. Emerging data from both human and animal models indicate that neural excitability is under circadian control. Diurnal changes in inhibition may drive this, as there is a relative increase in levels of cortical inhibition during the inactive phase corresponding to lower cortical excitability. Parvalbumin- positive (PV) interneurons are one of the most abundant interneuron types in the hippocampus and cortex; however, they are one of the multiple subtypes of inhibitory interneurons derived from the medial ganglionic eminence that interact to maintain cortical network dynamics. Preliminary data suggests altered clock gene expression in PV interneurons, increased epileptiform activity, and behavioral disinhibition in the hAPPJ20 model. Many important questions remain, including the functional and molecular mechanisms in MGE-derived inhibitory interneurons that contribute to circadian- and tau-mediated EA in AD models with increased levels of APP/Aβ. Thus, the current proposal will test the novel concept that circadian rhythms in cortical MGE-derived interneurons play a critical role in modulating network excitability and behavior. My overarching hypothesis is that altered clock gene rhythms in MGE-CINs contribute to network hyperexcitability and behavioral abnormalities, which can be corrected by tau reduction. I will test this hypothesis using single-molecule fluorescent in situ hybridization to quantify clock-gene transcript expression, electroencephalography to assess network hyperexcitability, and machine learning pipelines to analyze open-field videos for behavior. For these studies I will use hAPPJ20 mice, a commonly used model of AD with overexpression of APP & Aβ crossed with Tau+/- mice for my experimental groups for Aim 1. I will use Lhx6-Cre mice crossed with Bmalfl/fl to create a line of mice with the circadian clock ablated in only cortical MGE-interneurons, which will then again be crossed with Tau+/- for Aim 2 experiments. Overall, the work proposed will provide insights into the circadian mechanisms driving network hyperexcitability and behavioral changes in AD.