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Kamyabi, Alireza

University of British Columbia

As the most abundant cell type in the brain, astrocytes play a key role in neural functions and form complex interacting networks with neural circuits in various brain regions. Although not electrically excitable, astrocytes exhibit a complex repertoire of intracellular Ca²⁺ dynamics. Rapid elevations in intracellular Ca²⁺ concentration, known as Ca²⁺ events, are postulated to be one of the main intracellular signaling pathways in astrocytes and are thought to mediate key astrocytic functions including neuromodulation and bidirectional control of arteriole diameter. Ca²⁺ events in astrocytes exhibit a variety of spatiotemporal properties – ranging from fast, transient, and localized microdomain Ca²⁺ sparks to network-wide Ca²⁺ wave propagations that span across the astrocytic network. The mechanisms underlying the spatiotemporal properties of Ca²⁺ events, importantly their propagation both intracellularly and in astrocytic networks, remain elusive. Theoretical studies of Ca²⁺ propagation in astrocytes have previously posited that IP₃₋dependent Ca²⁺-induced Ca²⁺ release driven by Phospholipase C delta proteins act as an important regulator of Ca²⁺ propagation in astrocytes. Here we investigate the contribution of Phospholipase C delta 4 (PLCD4) to Ca²⁺ dynamics in astrocytes and demonstrate that PLCD4 is functionally expressed in the brain and in astrocytes. Using PLCD4-/- mice, we demonstrate that PLCD4 is an essential mediator of Ca²⁺ release from intracellular Ca²⁺ stores and acts to prolong and enhance IP₃₋mediated Ca²⁺ release following G𝑞-linked GPCR activation. Furthermore, we show that PLCD4 activity contributes to regulating the propagation and size of Ca²⁺ events in astrocytes. In PLCD-/- mice, astrocyte Ca²⁺ sparks exhibit reduced propagation and are smaller in size compared to sparks in PLCD4+/+ mice. Lastly, we report that network-wide Ca²⁺ wave propagations are still present in PLCD4-/- mice. Together, this data suggests that PLCD4 in astrocytes plays an important functional role in regulating Ca²⁺ release from the ER and acts as a secondary enhancer of astrocytic Ca²⁺ events. Subsequently, these findings suggest that PLCD4 may play a role in regulating Ca²⁺-mediated functions and paves the way for future studies to investigate the functional role of Ca²⁺ propagation in astrocytes.

Text

2022-04-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81269

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/