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) 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 (3alpha,5alpha)-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.
Xu
W
W
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cormier
R
R
Fu
T
T
Covey
D F
DF
Isenberg
K E
KE
Zorumski
C F
CF
Mennerick
S
S
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology
D002120:Calcium Channel Agonists; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium