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Examining the Role of Astrocyte Swelling and Swelling-Induced Glutamate Release in Two Models of Neuronal Hyperexcitability

  • Author(s): Murphy, Thomas R.
  • Advisor(s): Fiacco, Todd A
  • et al.
Abstract

Epilepsy, a spectrum of over 40 different disorders, is estimated to affect 1 in 26 people worldwide. It is generally characterized by the appearance of spontaneous, recurrent and unpredictable seizures. Approximately one-third of epileptic patients cannot control their seizures with current medications, while the remaining two-thirds of patients often experience negative cognitive side effects, highlighting the need to better understand epilepsy mechanisms. A common theme in multiple seizure models is that cellular swelling is necessary for seizure initiation and recurrence. In experiments described in this dissertation, I set out to determine: 1) The extent to which neurons and astrocytes swell in two experimental conditions that lead to neuronal bursting and epileptiform activity; 2) The mechanisms governing neuronal vs. astrocyte swelling; and 3) The contribution of astrocytes, specifically, to increases in neuronal excitability. These experiments were carried out in acute hippocampal slices from wild type and transgenic mice using a combination of electrophysiology and imaging approaches. The main findings from these studies were as follows: 1) Both reduced extracellular osmolarity and elevations of extracellular potassium ions ([K+]o) elevated neuronal excitability within minutes in an NMDA receptor-dependent manner; 2) Contrary to published reports, neurons are not osmoresistant and swell just as readily as astrocytes in hypoosmolar conditions, while astrocytes swell selectively in elevated [K+]o conditions; 3) Neuronal swelling is not an artifact of our experimental approaches, nor is it a result of NMDA receptor-driven excitotoxicity; and 4) Astrocytic volume-regulated anion channels (VRAC) may contribute to increased excitability of neurons through release of glutamate. Taken together, these findings have important implications for seizure disorders and for understanding the scope of neuron-glial interactions in the brain.

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