PROJECT SUMMARY
Converging evidence indicates that neuronal and network hyperexcitability is an important early event in
Alzheimer disease (AD) patients. The cellular and molecular basis of this hyperexcitability is a critical area of
investigation and the presence of similar hyperexcitability in animal models enables studies to dissect
underlying mechanisms. A key insight is that hyperexcitability in both AD patients and mouse models has a
strong diurnal rhythm. Emerging data from both humans and animal models indicate that neural excitability in
the forebrain is under circadian control, altering seizure thresholds and epileptiform activity. Circadian variation
in cellular function is driven by transcriptional molecular clocks expressed in most cells, and molecular clock
ablation increases AD pathology. We have compelling preliminary evidence for rhythmic variation in neuronal
excitability that is at least partly due to circadian regulation of the membrane properties of inhibitory
interneurons, especially fast-spiking cells that express parvalbumin – a cell type implicated in AD. Given that
molecular and physiological rhythms in hippocampus are disrupted in AD patients and AD mouse models, we
propose rigorous experiments to test the hypothesis that dysregulation of the molecular clock and resulting
changes in PV+ interneuron gene expression and activity contributes to AD-related neuronal hyperexcitability.
Specifically, we will evaluate the differences in circadian clock and clock-controlled gene expression in PV+
interneurons in a mouse model of AD, using a combination of RNA sequencing, state-of-the-art bioinformatics,
and recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific manner
(Aim 1). We will use patch-clamp electrophysiology to determine if AD-related impairment of the circadian clock
alters day-night differences in neurophysiological properties of PV+ interneurons, causing hyperexcitability
(Aim 2). Finally, we will utilize an innovative chemogenetic chronotherapeutic approach to manipulate PV+
interneuron physiology to determine whether reinstating the normal circadian regulation of PV+ interneuron
electrophysiological properties protects against AD-related hyperexcitability, cognitive impairment, and
pathology (Aim 3). The proposed studies led by a strong interdisciplinary team uses powerful approaches to
determine how disruption of circadian rhythms facilitates neuronal hyperexcitability that contributes to early
stages of AD. Understanding these mechanisms may catalyze development of behavioral or pharmacologic
interventions.