Circadian dysfunction and GSK3 in neurodegenerative disease

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DESCRIPTION (provided by applicant): Behavioral disturbance and day-night rhythm disruption of dementia patients are top reasons for institutionalization and cause of caregiver burden. Patients with dementia or Alzheimer's disease often exhibit "sundowning syndrome," a constellation of symptoms including late afternoon/evening hyperactivity, restlessness, confusion, and aggression, along with misaligned core body temperature and activity rhythms. These symptoms suggest a dysregulated circadian network, which normally allows anticipation of and preparation for daily recurring environmental events, including time-of-day-specific variability in cognitive function. Identification of the molecular abnormalities underlying circadin dysregulation would allow for the development of targeted strategies for reinstating rhythmicity and associated behaviors. This project will test the hypothesis that glycogen synthase kinase 3 provides a time-of-day-specific gating mechanism for intrinsic excitability, and that disruptions i daily changes in the phosphorylation state balance of this enzyme within specific brain regions contribute to circadian and cognitive abnormalities of neurodegenerative disease. Specifically, this project will determine whether day-night changes in phosphorylation of glycogen synthase kinase 3 regulate oscillations of clock gene expression and physiology and that cognition and circadian behavioral abnormalities in neurodegenerative disease are mediated by loss of daily glycogen synthase kinase 3 phosphorylation cycles and dysregulated neural activity rhythms. Proposed studies will examine this hypothesis in the suprachiasmatic nucleus and hippocampus under normal physiologic conditions (Aim 1) as well as under pathological conditions (Aim 2) utilizing animal models of neurodegenerative disease. Successful completion of these experiments will establish glycogen synthase kinase 3 as a key player in day-night variation of membrane properties and synaptic physiology, which are critical for appropriately timed cognitive function and rest/activity patterns. They will also lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing in dementia and neurological disease.