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

NEUROBIOLOGY OF DISEASE

卷:81

Article

Gilad, David¹  Shorer, Sharon¹  Ketzef, Maya¹  Friedman, Alon¹  Sekler, Israel¹  Aizenman, Elias^1,2  Hershfinkel, Michal¹ 

[1] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Physiol & Cell Biol, IL-84015 Beer Sheva, Israel

[2] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA USA

关键词: Epilepsy;    Seizure;    Hippocampus;    Zinc receptor;    m2nR/GPR39;    KCC2;    Kainic acid;   

DOI  :  10.1016/j.nbd.2014.12.020

来源: Elsevier

【 摘 要 】

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- cotransporter 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 Gaq/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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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