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The Journal of Neuroscience, May 1, 2000, 20(9):3147-3156

Slow Death of Postnatal Hippocampal Neurons by GABA_A Receptor Overactivation

Wanyan Xu¹, Robert Cormier¹, Tao Fu¹, Douglas F. Covey², Keith E. Isenberg¹, Charles F. Zorumski^{1, 3}, and Steven Mennerick^{1, 3}

Departments of ¹ Psychiatry, ² Molecular Biology and Pharmacology, and ³ Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABA_A receptor activity for 5-8 d in vitro enhanced survival of hippocampal neurons, suggesting that GABA_A receptor overactivation may be neurotoxic. Potentiating GABA_A receptor activity by chronic treatment with the endogenous neurosteroid (3,5)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABA_A receptors, including benzodiazepines, mimicked the cell loss, suggesting that potentiating endogenous GABA activity is sufficient to produce neuronal death. Neurosteroid-treated neurons had lower resting intracellular calcium levels than control cells and produced smaller calcium rises in response to depolarizing challenges. Manipulating intracellular calcium levels with chronic elevated extracellular potassium or with the calcium channel agonist Bay K 8644 protected neurons. The results may have implications for the mechanisms of programmed cell death in the developing CNS as well as implications for the long-term consequences of chronic GABAmimetic drug use during development.

Key words: GABA; calcium; toxicity; apoptosis; benzodiazepine; neurosteroid

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2093147-10$05.00/0

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