Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

David Gilad, Sharon Shorer, Maya Ketzef, Alon Friedman, Israel Sekler, Elias Aizenman, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K+/Cl- co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn2+ chelation. Importantly, kainate-induced synaptic Zn2+ release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity.

Original languageEnglish
Pages (from-to)4-13
Number of pages10
JournalNeurobiology of Disease
StatePublished - 1 Sep 2015


  • Epilepsy
  • Hippocampus
  • KCC2
  • Kainic acid
  • MZnR/GPR39
  • Seizure
  • Zinc receptor

ASJC Scopus subject areas

  • Neurology


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