Astrocytes are key players in regulating neuronal excitability and neurotransmission. We have recently shown that astrocytes participate in brain functions thrugh ?team-work?. Specifically, a strong gap junction coupling, astrocytes achieve a state of syncytial isopotentiality across the brain that is crucial for potassium homeostasis. Now our new studies further show that acute disruption of syncytial isopotentiality impairs neuronal excitability nad synaptic transmision. However, our understanding is still in its infancy with respect to how the syncytial isopotentiality is established and dynamically regulated through crosstalk with neuronal signals. To begin to gain insight into this system-wide electrical feature of the astrocyte network, the objective of this proposal will be mostly focused on how neuronal signalings regulate syncytial isopotentiality. Our new studies show that intracellular Ca2+ ([Ca2+]i) is a key regulator of the electrical coupling of astrocyte syncytium. Also through regulating [Ca2+]i, glutamate potentiates electrical coupling of astrocyte syncytial coupling. At the basal physiological level, norepinephrine signaling is indicated to bidirectionally regulate the set point strength of astrocyte coupling through Gq-coupled ?1-adrenergic receptors (?1-AR). Thus, we hypothesize that neuronal norepinephrine signaling establishes the set point of syncytial coupling, whereas glutamatergic signaling induces a novel form of glioplasity for potentiation of astrocyte syncytial coupling. Our first specific aim will establish the role of [Ca2+]i in bidirectionally regulating the electrical coupling of astrocyte syncytium. The electrophysiology and chemogentics with astrocytic expression of Gq-DREADD will be used in these studies.
The second aim will determine the mechanism underlying a glutamatergic signaling- induced potentiation of syncytial coupling. Hippocampal CA3?CA1 glutamatergic transmission will be activated in wildtype and conditional Cx43 knockout (hGfap-Cre:Cx43flox/flox) mice to validate that this glial network plasticity is mediated through Cx43 in an [Ca2+]i-dependent fashion.
The third aim will determine the role of norepinephrine signaling in establishing a set point strength of astrocyte syncytial coupling. This hypothesis will be examined through pharmacologial and genetic manipulation of astrocytic ?1-AR. The completion of this project is expected to validate the view that astrocyte syncytium indeed interacts as a functional system with neuronal signaling. We expect to uncover the molecular mechanisms underlying the regulation of the basic and plasticity of astrocyte syncytial coupling. Ultimately, these results are expected to shed light on a new research direction, in which the mysterious function of astrocytes can be explored at a biologically higher hierarchy, the level of the syncytial system. This work in healthy CNS lays the foundation for exploring how alteration of astrocyte syncytium etiologically contributes to diseased and injured brains.

Public Health Relevance

Astrocytes establish a functional network system through conduit proteins, termed gap junctions, to participate in brain function. This proposal is expected to provide novel insights into the physiological operation of this glial network system through crosstalk with neuronal signalings. By examining astrocyte function at a biologically higher hierarchy, a networking system level, the results are expected to shed light on the still mysterious function of astrocytes, and also establish dataset for further examination of the potential etiological link between dysfunctional astrocyte networks and neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS116059-02
Application #
10112976
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Leenders, Miriam
Project Start
2020-03-01
Project End
2025-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210