GABA Synapses Mediate Neuroprotection after Ischemic and εPKC Preconditioning in Rat Hippocampal Slice Cultures

Author:

DeFazio R. Anthony1,Raval Ami P1,Lin Hung W1,Dave Kunjan R1,Della-Morte David1,Perez-Pinzon Miguel A1

Affiliation:

1. Cerebral Vascular Disease Research Center, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA

Abstract

Delayed neuroprotection against ischemic challenges is conferred by both ischemic preconditioning (IPC) and preconditioning by activation of the ε-isoform of protein kinase C (εPKC-PC). In vivo, ischemic preconditioning enhances GABA release and ameliorates glutamate release during lethal cerebral ischemia. We tested the hypothesis that IPC and εPKC-PC confer neuroprotection by GABA synapses in rat organotypic hippocampal slices. Ischemic preconditioning or εPKC-PC was induced with 15 mins oxygen-glucose deprivation (OGD) or ψεRACK, a selective εPKC activator; and test ischemia consisted of 40 mins OGD. At the time of peak neuroprotection (48 h after preconditioning), we recorded GABAA receptor-mediated miniature postsynaptic currents (GABA mPSCs) in vulnerable CA1 pyramidal neurons using whole-cell voltage clamp techniques. The frequency and amplitude of GABA mPSCs significantly increased 48 h after IPC. In contrast, εPKC-PC enhanced only the amplitude of GABA mPSCs with no effect on frequency. We next asked if neuroprotection depended on these changes in GABA synapses. Weak antagonism of the GABAA receptor with bicuculline (100 nmol/L) decreased the amplitude of GABA mPSCs by 20.9±6.1%. When applied during test ischemia, 100nmol/L bicuculline abolished neuroprotection conferred by either IPC or εPKC-PC. We conclude that neuroprotection conferred by preconditioning depends on functional modifications of GABA synapses.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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