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The Regulation of Aquaporin-4 (AQP4) and Glutamate Transporter-1 (GLT1) in an Epilepsy Model

  • Author(s): Hubbard, Jacqueline Ann
  • Advisor(s): Binder, Devin K
  • et al.
Creative Commons Attribution 4.0 International Public License
Abstract

Epilepsy is a group of chronic neurological disorders characterized by abnormally synchronized activity among neurons that presents as seizures. It is a major health problem that is estimated to affect 1 in 26 people during their lifetime. Many antiepileptic drugs (AEDs) currently exist, but approximately 30% of patients taking AEDs cannot control their seizures with drugs alone. In addition, adverse effects such as cognitive impairment are common. This may be because current AEDs act as central nervous system depressants and target neuronal channels to control tissue excitability. Therefore, new drugs based on non-neuronal targets may serve as novel therapeutic strategies with fewer deleterious effects. Astrocytes maintain glutamate and water homeostasis primarily through glutamate transporters and aquaporin-4 (AQP4), respectively. The two astrocyte-specific glutamate transporters are glutamate transporter-1 (GLT1) and glutamate aspartate transporter (GLAST), of which GLT1 is responsible for the majority of glutamate uptake in the forebrain. Alterations in both glutamate and water homeostasis have powerful effects on excitability, but the regulation of GLT1, GLAST, and AQP4 in epilepsy is not well understood. Furthermore, the β-lactam antibiotic ceftriaxone has previously been shown to upregulate GLT1 expression, but its efficacy in a chronic epilepsy model has not been well studied. Here I describe AQP4, GLT1, and GLAST hippocampal expression changes in a model of epilepsy. I begin by characterizing the intrahippocampal kainic acid (IHKA) model of epilepsy, focusing on astrocyte reactivity during the development of epilepsy (epileptogenesis). I then describe the highly polarized AQP4 expression in the healthy brain and show reduced hippocampal levels during epileptogenesis. After that, I discuss alterations of GLT1 levels after IHKA-induced epileptogenesis. Next, I discuss the lack of effect of β-lactam drugs on regulating AQP4 and GLT1 expression, thereby eliminating it as a potential antiepileptic therapeutic. I then describe the co-localization patterns of AQP4 and GLT1; these two proteins do not co-immunoprecipitate, suggesting the lack of a strong interaction between them. In the penultimate chapter, I briefly describe the minimal changes in GLAST expression during epileptogenesis. I conclude with a summary of my findings and suggested future directions for this line of research.

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