Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity

Exp Neurol. 2019 Aug;318:50-60. doi: 10.1016/j.expneurol.2019.04.010. Epub 2019 Apr 22.


The contribution of glial transporters to glutamate movement across the membrane has been identified as a potential target for anti-seizure therapies. Two such glutamate transporters, GLT-1 and system xc-, are expressed on glial cells, and modulation of their expression and function have been identified as a means by which seizures, neuronal injury, and gliosis can be reduced in models of brain injury. While GLT-1 is responsible for the majority of glutamate uptake in the brain, system xc- releases glutamate in the extracellular cleft in exchange for cystine and represents as such the major source of hippocampal extracellular glutamate. Using the Theiler's Murine Encephalomyelitis Virus (TMEV) model of viral-induced epilepsy, we have taken two well-studied approaches, one pharmacological, one genetic, to investigate the potential role(s) of GLT-1 and system xc- in TMEV-induced pathology. Our findings suggest that the methods we utilized to modulate these glial transporters, while effective in other models, are not sufficient to reduce the number or severity of behavioral seizures in TMEV-infected mice. However, genetic knockout of xCT, the specific subunit of system xc-, may have cellular effects, as we observed a slight decrease in neuronal injury caused by TMEV and an increase in astrogliosis in the CA1 region of the hippocampus. Furthermore, xCT knockout caused an increase in GLT-1 expression selectively in the cortex. These findings have significant implications for both the characterization of the TMEV model as well as for future efforts to discover novel and effective anti-seizure drugs.

Keywords: Epilepsy; GLT-1; Glia; Glutamate transporters; System x(c)(−); Theiler's Murine Encephalomyelitis Virus (TMEV); xCT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / metabolism*
  • Animals
  • Brain / pathology
  • Cardiovirus Infections / complications
  • Cardiovirus Infections / pathology
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Seizures / metabolism*
  • Seizures / pathology
  • Seizures / virology
  • Theilovirus


  • Amino Acid Transport System y+
  • Excitatory Amino Acid Transporter 2
  • Slc1a2 protein, mouse
  • Slc7a11 protein, mouse