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Principal Investigator: MIN ZHOU
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $346,725
Funding agency: National Institute of Neurological Disorders and Stroke
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 α1-adrenergic receptors (α1-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 α1-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.
Terms: <Acquired brain injury><Acute><Adrenergic Receptor><Adrenoceptors><Ammon Horn><Astrocytes><Astrocytus><Astroglia><Autoregulation><Biological><Brain><Brain Injuries><Brain Nervous System><Causality><Cell Communication and Signaling><Cell Signaling><Chemosensitization><Chemosensitization/Potentiation><Clozapine><Communicating Junction><Connexin 43><Connexin43><Cornu Ammonis><Coupled><Coupling><Cx43><DREADDs><Data><Data Set><Dependence><Disease><Disorder><Dissociation><Dose><Electrophysiology><Electrophysiology (science)><Encephalon><Epinephrine Receptors><Etiology><Foundations><Gap Junctions><Giant Cells><Glutamate Translocase><Glutamate Transport Glycoprotein><Glutamate Transporter><Glutamates><Hippocampus><Homeostasis><Impairment><In Situ><Intracellular Communication and Signaling><K channel><K element><Knock-out><Knockout><L-Glutamate><Levarterenol><Levonorepinephrine><Link><Low-resistance Junction><LoxP-flanked allele><Mediating><Mediator><Methods><Mice><Mice Mammals><Molecular><Multinucleated Giant Cells><Murine><Mus><Mutant Strains Mice><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Transmission><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Nexus Junction><Noradrenaline><Norepinephrine><Physiologic><Physiological><Physiological Homeostasis><Polykaryocytes><Potassium><Potassium Channel><Potassium Ion Channels><Potentiation><Proteins><Regulation><Research><Role><Series><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Synaptic Transmission><Syncytium><System><Testing><Transmission><Tzanck Cell><Work><adenoreceptor><astrocytic glia><axon signaling><axon-glial signaling><axonal signaling><biologic><biological signal transduction><brain damage><brain-injured><causation><designer receptors exclusively activated by designer drugs><disease causation><dosage><electrophysiological><floxed><floxed allele><functional plasticity><gap junction channel><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glia signaling><glial signaling><glutamate signaling><glutamatergic><glutamatergic dendrodendritic synapses><glutamatergic signaling><hippocampal><infancy><infantile><insight><mouse mutant><nerve signaling><neural signaling><neurological disease><neuronal><neuronal excitability><neuronal signaling><neurotransmission><novel><operation><operations><patch clamp><pharmacologic><response><short-term potentiation><social role><transmission process>