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The Journal of Neuroscience, May 5, 2004, 24(18):4478-4488; doi:10.1523/JNEUROSCI.0755-04.2004
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Neurobiology of Disease
Changes in Intracellular Chloride after Oxygen–Glucose Deprivation of the Adult Hippocampal Slice: Effect of Diazepam
Francesca Galeffi, Renu Sah, Brooks B. Pond, Amanda George, andRochelle D. Schwartz-Bloom Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
Ischemic injury to the CNS results in loss of ionic homeostasis and the development of neuronal death. An increase in intracellular Ca2+ is well established, but there are few studies of changes in intracellular Cl– ([Cl–]i) after ischemia. We used an in vitro model of cerebral ischemia (oxygen–glucose deprivation) to examine changes in [Cl–]i and GABAA receptor-mediated responses in hippocampal slices from adult rats. Changes in [Cl–]i were measured in area CA1 pyramidal neurons using optical imaging of 6-methoxy-N-ethylquinolinium chloride, a Cl–-sensitive fluorescent indicator. Oxygen–glucose deprivation induced an immediate rise in [Cl–]i, which recovered within 20 min. A second and more prolonged rise in [Cl–]i occurred within the next hour, during which postsynaptic field potentials failed to recover. The sustained increase in [Cl–]i was not blocked by GABAA receptor antagonists. However, oxygen–glucose deprivation caused a progressive downregulation of the K+–Cl– cotransporter (KCC2), which may have contributed to the Cl– accumulation. The rise in [Cl–]i was accompanied by an inability of the GABAA agonist muscimol to cause Cl– influx. In vivo, diazepam is neuroprotective when given early after ischemia, although the mechanism by which this occurs is not well understood. Here, we added diazepam early after oxygen–glucose deprivation and prevented the downregulation of KCC2 and the accumulation of [Cl–]i. Consequently, both GABAA responses and synaptic transmission within the hippocampus were restored. Thus, after oxygen–glucose deprivation, diazepam may decrease neuronal excitability, thereby reducing the energy demands of the neuron. This may prevent the activation of downstream cell death mechanisms and restore Cl– homeostasis and neuronal function.
Key words: ischemia; GABAA receptor; MEQ; KCC2; Cl–-ATPase; benzodiazepines
Received Dec 18, 2003; revised March 31, 2004; accepted April 1, 2004.
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