RT Journal Article SR Electronic T1 Slow Death of Postnatal Hippocampal Neurons by GABAA Receptor Overactivation JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3147 OP 3156 DO 10.1523/JNEUROSCI.20-09-03147.2000 VO 20 IS 9 A1 Xu, Wanyan A1 Cormier, Robert A1 Fu, Tao A1 Covey, Douglas F. A1 Isenberg, Keith E. A1 Zorumski, Charles F. A1 Mennerick, Steven YR 2000 UL http://www.jneurosci.org/content/20/9/3147.abstract AB Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABAA receptor activity for 5–8 d in vitro enhanced survival of hippocampal neurons, suggesting that GABAA receptor overactivation may be neurotoxic. Potentiating GABAA receptor activity by chronic treatment with the endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABAA 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.