Slow death of postnatal hippocampal neurons by GABA(A) receptor overactivation

Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABA(A) r eceptor activity for 5-8 d in vitro enhanced survival of hippocampal neuron s, suggesting that GABA(A) receptor overactivation may be neurotoxic. Poten tiating GABA(A) receptor activity by chronic treatment with the endogenous neurosteroid (3 alpha,5 alpha)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABA(A) receptors, inclu ding benzodiazepines, mimicked the cell loss, suggesting that potentiating endogenous GABA activity is sufficient to produce neuronal death. Neuroster oid-treated neurons had lower resting intracellular calcium levels than con trol cells and produced smaller calcium rises in response to depolarizing c hallenges. Manipulating intracellular calcium levels with chronic elevated extracellular potassium or with the calcium channel agonist Bay K 8644 prot ected neurons. The results may have implications for the mechanisms of prog rammed cell death in the developing CNS as well as implications for the lon g-term consequences of chronic GABAmimetic drug use during development.