Friday, May 9, 2025
5/9/2025
Mechanisms of astrocyte volume regulation and control of neural excitability - PROJECT SUMMARY The volume-regulated anion channel (VRAC) is an outwardly rectifying anion channel that is activated in response to cell swelling to initiate homeostatic regulation of cell volume. Upon opening, VRAC release Cl- and other anions as well as negatively-charged osmolytes including glutamate into the extracellular space (ECS) to initiate volume regulation in the cell. In brain, astrocytes have been found to regulate the ECS and its contents through dynamic fluctuations in cell volume that correlate with sleep, consciousness, alertness, and levels of synaptic activity. Therefore, VRAC may be especially important in astrocytes for regulation of brain tissue excitability. Evidence suggests that astrocytic VRAC release glutamate in conditions of cell swelling, contributing to ambient glutamate concentrations, stimulation of neuronal glutamate receptors, and excitotoxic cell death in models of stroke. In epilepsy, it has been known for many years that cell swelling is critical for the initiation and recurrence of seizures. Surprisingly, however, the role of VRAC in network excitability, epileptiform activity, epileptogenesis, and seizure generation and severity has never been directly tested. The long-term goal of our research is to identify molecular mechanisms of brain tissue excitability and epilepsy. The objective here is to determine the contribution of astrocytic VRAC to neuronal network excitability, seizure generation and epileptogenesis using astrocyte- specific conditional VRAC knockout (VRAC cKO). Our central hypothesis is that astrocytic VRAC significantly contribute to seizure generation, epileptiform activity, development of epilepsy, and pathology associated with epilepsy including hippocampal sclerosis and neuronal cell loss through swelling-activated release of glutamate. The rationale for the proposed research is that generation of new knowledge on epilepsy mechanisms will lead to development of new therapeutic targets with fewer cognitive side effects. First, we will determine the contribution of astrocytic VRAC in brain tissue swelling and seizure generation in vivo. Second, we will measure the involvement and therapeutic potential of astrocytic VRAC in the development of epilepsy using a combination of VRAC overexpression and rescue strategies in VRAC cKO mice. Third, we will identify mechanisms of VRAC-mediated excitability changes and role in astrocyte volume regulation at the cellular level. At the conclusion of these studies, it is our expectation that we will have generated valuable new knowledge on astrocytic VRAC and its role in hyperexcitability, cell volume regulation, seizure generation and epileptogenesis in situ and in vivo. These results are anticipated to have positive impact by fundamentally advancing understanding of cell volume regulation, mechanisms of glutamate release, and glial-neuronal interactions, while also providing novel targets for the treatment of seizure disorders, excitotoxicity and epilepsy.
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