EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia

J Neurosci. 2010 Nov 17;30(46):15409-18. doi: 10.1523/JNEUROSCI.2084-10.2010.


EAAC1 is a neuronal glutamate and cysteine transporter. EAAC1 uptake of cysteine provides substrate for neuronal glutathione synthesis, which plays a key role in both antioxidant defenses and intracellular zinc binding. Here we evaluated the role of EAAC1 in neuronal resistance to ischemia. EAAC1(-/-) mice subjected to transient cerebral ischemia exhibited twice as much hippocampal neuronal death as wild-type mice and a corresponding increase in microglial activation. EAAC1(-/-) mice also had elevated vesicular and cytosolic zinc concentrations in hippocampal CA1 neurons and an increased zinc translocation to postsynaptic neurons after ischemia. Treatment of the EAAC1(-/-) mice with N-acetyl cysteine restored neuronal glutathione concentrations and normalized basal zinc levels in the EAAC1(-/-) mice. Treatment of the EAAC1(-/-) mice with either N-acetyl cysteine or with zinc chelators reduced ischemia-induced zinc translocation, superoxide production, and neuron death. These findings suggest that cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function under ischemic conditions.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcysteine / metabolism
  • Animals
  • Disease Progression*
  • Excitatory Amino Acid Transporter 3 / deficiency
  • Excitatory Amino Acid Transporter 3 / genetics*
  • Gene Deletion*
  • Homeostasis / genetics*
  • Ischemic Attack, Transient / genetics*
  • Ischemic Attack, Transient / metabolism
  • Ischemic Attack, Transient / pathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / pathology*
  • Zinc / physiology*


  • Excitatory Amino Acid Transporter 3
  • Slc1a1 protein, mouse
  • Zinc
  • Acetylcysteine