 |
 Previous Article | Next Article 
The Journal of Neuroscience, May 1, 2000, 20(9):3147-3156
Slow Death of Postnatal Hippocampal Neurons by
GABAA Receptor Overactivation
Wanyan
Xu1,
Robert
Cormier1,
Tao
Fu1,
Douglas F.
Covey2,
Keith E.
Isenberg1,
Charles F.
Zorumski1, 3, and
Steven
Mennerick1, 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 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 (3 ,5)-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.
Key words:
GABA; calcium; toxicity; apoptosis; benzodiazepine; neurosteroid
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093147-10$05.00/0
This article has been cited by other articles:
|
|
|
|
 
A. Azimi-Zonooz, C. W. Shuttleworth, and J. A. Connor
GABAergic Protection of Hippocampal Pyramidal Neurons Against Glutamate Insult: Deficit in Young Animals Compared to Adults
J Neurophysiol,
July 1, 2006;
96(1):
299 - 308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Moulder, X. Jiang, A. A. Taylor, J. W. Olney, and S. Mennerick
Physiological activity depresses synaptic function through an effect on vesicle priming.
J. Neurosci.,
June 14, 2006;
26(24):
6618 - 6626.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Moulder, R. J. Cormier, A. A. Shute, C. F. Zorumski, and S. Mennerick
Homeostatic Effects of Depolarization on Ca2+ Influx, Synaptic Signaling, and Survival
J. Neurosci.,
March 1, 2003;
23(5):
1825 - 1831.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Grobin, E. J. Heenan, J. A. Lieberman, and A. L. Morrow
Perinatal Neurosteroid Levels Influence GABAergic Interneuron Localization in Adult Rat Prefrontal Cortex
J. Neurosci.,
March 1, 2003;
23(5):
1832 - 1839.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Auger, T. S. Perrot-Sinal, and M. M. McCarthy
Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain
PNAS,
June 20, 2001;
(2001)
131016298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. S. Perrot-Sinal, A. M. Davis, K. A. Gregerson, J. P. Y. Kao, and M. M. McCarthy
Estradiol Enhances Excitatory Gammabutyric Acid-Mediated Calcium Signaling in Neonatal Hypothalamic Neurons
Endocrinology,
June 1, 2001;
142(6):
2238 - 2243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Auger, T. S. Perrot-Sinal, and M. M. McCarthy
Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain
PNAS,
July 3, 2001;
98(14):
8059 - 8064.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
