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Journal of Neuroscience, Vol 14, 2763-2774, Copyright © 1994 by Society for Neuroscience
The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons
RD Brinton
Department of Molecular Pharmacology and Toxicology, University of Southern California Pharmaceutical Sciences Center, Los Angeles 90033.
The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5
alpha-THP) acts as a potent allosteric modulator and a direct activator of
the GABA-chloride channel complex. This neurosteroid has also been found to
protect against seizures that arise from blockade of the GABA- chloride
channel complex. Because 3 alpha,5 alpha-THP protects against
excitotoxin-induced seizure activity and because seizure activity has been
found to be associated with aberrant hippocampal nerve cell growth, the
rapid effect of the neurosteroid 3 alpha,5 alpha-THP upon nerve cell growth
was investigated using videomicroscopy of hippocampal neurons in culture.
Within 40 min of exposure 3 alpha,5 alpha-THP induced a significant
decrease in the area and length of neurites. A concomitant decrement in the
number and length of filopodia decorating neuritic extensions also occurred
within the 40 min of 3 alpha,5 alpha- THP exposure. Both rapid and slow
retrograde movement of intracellular organelles was observed in 3 alpha,5
alpha-THP-treated neurons. 3 alpha,5 alpha-THP-induced regression of
neuritic extensions occurred only in nerve cells that had not yet
established contact with other nerve or glial cells in culture. Established
structural connections between neurons or glia did not erode during 3
alpha,5 alpha-THP exposure. Neither the inactive stereoisomer 3
beta-hydroxy-5 beta- pregnan-20-one nor progesterone had a significant
effect upon any of the morphological parameters assessed. In approximately
25% of the cells in which 3 alpha,5 alpha-THP had induced regression,
subsequent exposure to 17 beta-estradiol induced profuse filopodial growth
within 60 sec of exposure. In cultures similar in age to those used in the
morphological studies, 3 alpha,5 alpha-THP induced a significant increase
in 36Cl- uptake within 10 sec. The magnitude of 36Cl- uptake was comparable
to that induced by exposure to 100 microM GABA. In older, more mature
cultures in which the nerve cells had established structural connections, 3
alpha,5 alpha-THP protected cells from picrotoxin-induced nerve cell death.
These results demonstrate that 3 alpha,5 alpha-THP can induce regression of
neuronal morphology within a relatively rapid time frame. 3 alpha,5
alpha-THP induction of 36Cl- uptake within 10 sec suggests that activation
of neurosteroid-regulated chloride channels is an initial step in the
biochemical mechanism underlying the retraction induced by this
progesterone metabolite steroid. In select instances, 17 beta-estradiol
induced an extremely rapid reversal of the filopodial regression produced
by 3 alpha,5 alpha- THP.(ABSTRACT TRUNCATED AT 400 WORDS)
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