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The Journal of Neuroscience, April 1, 1998, 18(7):2550-2559
Estradiol Increases Dendritic Spine Density by Reducing GABA
Neurotransmission in Hippocampal Neurons
Diane D.
Murphy1,
Nelson B.
Cole2,
V.
Greenberger3, and
Menahem
Segal3
1 Laboratory of Neurobiology, National Institute of
Neurological Diseases and Stroke, and 2 Cell Biology and
Metabolism Branch, National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland 20892, and 3 Department of Neurobiology, The Weizmann Institute,
Rehovot, 71600 Israel
We have previously shown that estradiol causes a twofold rise in
dendritic spine density in cultured rat hippocampal neurons, as it does
in vivo. More recently, estrogen receptors have been localized to aspiny inhibitory hippocampal interneurons, indicating that their effect on spiny pyramidal neurons may be indirect. We
therefore examined the possibility that estradiol affects spine density
by regulating inhibition in cultured hippocampal interneurons. Immunocytochemically, estrogen receptors were found to be co-localized with glutamate decarboxylase (GAD)-positive neurons (~21% of total neurons in the culture). Exposure of cultures to estradiol for 1 d
caused a marked decrease (up to 80%) in the GAD content of the
interneurons, measured both by immunohistochemistry and Western blotting. Also, the number of GAD-positive neurons in the cultures decreased to 12% of the total cell population. Moreover, GABAergic miniature IPSCs were reduced in both size and frequency by estradiol, whereas miniature EPSCs increased in frequency. We then mimicked the
proposed effects of estradiol by blocking GABA synthesis with mercaptopropionic acid (MA). Cultures treated with MA expressed a
dose-dependent decrease in GABA immunostaining that mimicked that seen
with estradiol. MA-treated cultures displayed a significant 50%
increase in dendritic spine density over controls, similar to that
produced by estradiol. These results indicate that estradiol decreases
GABAergic inhibition in the hippocampus, which appears to effectively
increase the excitatory drive on pyramidal cells, and thus may provide
a mechanism for formation of new dendritic spines.
Key words:
hippocampus; dendritic spines; interneuron; estrogen
receptors; GABA; cultures
Copyright © 1998 Society for Neuroscience 0270-6474/98/1872550-10$05.00/0
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