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The Journal of Neuroscience, April 14, 2004, 24(15):3837-3849; doi:10.1523/JNEUROSCI.5539-03.2004

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Neurobiology of Disease
Sequential Release of GABA by Exocytosis and Reversed Uptake Leads to Neuronal Swelling in Simulated Ischemia of Hippocampal Slices

Nicola J. Allen,¹ David J. Rossi,² and David Attwell¹

¹Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and ²Neurological Sciences Institute, Oregon Health Sciences University, Beaverton, Oregon 97006

GABA release during cerebral energy deprivation (produced by anoxia or ischemia) has been suggested either to be neuroprotective, because GABA will hyperpolarize neurons and reduce release of excitotoxic glutamate, or to be neurotoxic, because activation of GABA_A receptors facilitates Cl^– entry into neurons and consequent cell swelling. We have used the GABA_A receptors of hippocampal area CA1 pyramidal cells to sense the rise of [GABA]_o occurring in simulated ischemia. Ischemia evoked, after several minutes, a large depolarization to –20 mV. Before this "anoxic depolarization," there was an increase in GABA release by exocytosis (spontaneous IPSCs). After the anoxic depolarization, there was a much larger, sustained release of GABA that was not affected by blocking action potentials, vesicular release, or the glial GABA transporter GAT-3 but was inhibited by blocking the neuronal GABA transporter GAT-1. Blocking GABA_A receptors resulted in a more positive anoxic depolarization but decreased cell swelling at the time of the anoxic depolarization. The influence of GABA_A receptors diminished in prolonged ischemia because glutamate release evoked by the anoxic depolarization inhibited GABA_A receptor function by causing calcium entry through NMDA receptors. These data show that ischemia releases GABA initially by exocytosis and then by reversal of GAT-1 transporters and that the resulting Cl^– influx through GABA_A receptor channels causes potentially neurotoxic cell swelling.

Key words: GABA; ischemia; chloride; transporter; GAT-1; excitotoxicity; reversed uptake

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Received Dec 16, 2003; revised March 8, 2004; accepted March 8, 2004.

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