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Calcium and CREB signaling coordinate astrocyte metabolism: implications for ischemic stroke
Dissertation

Calcium and CREB signaling coordinate astrocyte metabolism: implications for ischemic stroke

Geena Kunjuveetil John
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2026
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John_Geena_20265.02 MB
PDF Embargoed Access, Embargo ends: 30 Sep 2028

Abstract

Biology Astrocytes Calcium cAMP response element-binding proteins Mitochondria Strokes Metabolism
Ischemic stroke remains a leading cause of death and long-term disability worldwide, yet effective therapeutic options remain limited. Astrocytes, which serve as essential homeostatic regulators of the central nervous system, are increasingly recognized as active regulators of the response to ischemic injury. The overarching goal of this dissertation was to identify astrocyte-specific molecular mechanisms that regulate cellular adaptation and may ultimately influence tissue survival following ischemic stroke. Following ischemic injury, astrocytic calcium signaling becomes prolonged, yet whether this response promotes tissue survival or contributes to injury remains unresolved. To address this question, we investigated whether enhancing calcium clearance would improve tissue survival following ischemia. Pharmacological inhibition identified plasma membrane calcium ATPases (PMCAs) as major regulators of spontaneous astrocytic calcium activity, while ischemic injury significantly reduced astrocytic PMCA2 expression during the hyperacute and acute phases of stroke. Although astrocyte-specific PMCA2 overexpression partially restored calcium extrusion, it unexpectedly exacerbated ischemia-induced cell death, suggesting that reduced PMCA2-mediated calcium clearance represents an adaptive astrocytic response to ischemic injury. Because sustained calcium signaling has the potential to engage longer-term transcriptional and metabolic adaptations, the second objective of this dissertation was to investigate the calcium-responsive transcription factor cAMP response element-binding protein (CREB) as a potential regulator of astrocyte metabolism. CREB activation promoted mitochondrial network remodeling, enhanced cellular bioenergetics, increased astrocyte growth, and strengthened astrocyte-synapse associations, identifying CREB as an important regulator of physiological astrocyte metabolic adaptation. Together, these findings establish PMCA2-mediated calcium clearance as a key regulator of astrocyte calcium signaling during ischemia and identify CREB as a central mediator of physiological mitochondrial remodeling and metabolic function. Collectively, this work provides a conceptual framework for understanding how adaptive remodeling of astrocyte calcium signaling may contribute to longer-term metabolic adaptation and highlights astrocyte-specific pathways that may ultimately be leveraged to improve tissue outcome following ischemic stroke.

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