Regulation of Synaptic Rhythmicity by Astrocytic Clock

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Cognitive deficits such as learning and memory impairments are common in people subjected to chronic disturbance of the circadian cycle due to shift work, travel, or genetic dysregulation of the circadian clock. Epidemiological studies have revealed a global rise in cognitive disorders with circadian disruptions comorbidity such as depression, and Alzheimer’s disease, stressing the need to identify the causal relationship between these phenomena. However, the molecular mechanisms linking the circadian cycle and cognitive performance in health and disease remain largely unresolved. Neuronal synapses are the cellular basis for learning and memory processes. Synapse number, activity, and expression levels of synaptic proteins show rhythmic time- of-day-dependent changes, yet how these changes are regulated by the circadian clock is poorly understood. A growing body of work supports a critical role for the glial cells, astrocytes in normal clock function. Astrocytes are important synaptic regulators, and key for establishment and maintenance of memory and learning. Yet, how the astrocytic clock regulates synaptic rhythmicity and related cognitive performance has not been thoroughly examined. This critical gap in knowledge must be addressed in order to understand not only the fundamental functions of the astrocytic clock, but also to characterize the regulatory mechanisms that control circadian changes in synaptic levels. This application will define the role of astrocytic clocks in regulating synaptic rhythmicity and subsequent learning and memory behaviors in three aims. Aim 1 investigates how the astrocytic clock expressed in brain regions responsible for cognitive processes (e.g., cortex, and hippocampus; outside the central clock located in the suprachiasmatic nucleus (SCN)), affects time-of-day-dependent changes in synapses and cognitive performance. Aim 2 investigates how the astrocytic clock is regulated by calcium activity to influence synaptic rhythmicity. In Aim 3, we test the hypothesis that astrocyte-derived synapse-regulating factors are rhythmically produced to facilitate time-of-day-dependent modulation of synapses. Successful completion of these aims will uncover the role of astrocytic clock in regulating synaptic and cognitive rhythms, and reveal strategies for future manipulation of synaptic rhythmicity through astrocyte-targeting, to restore clock-associated cognitive deficits prevalent in neurological disorders.