blackwell-synergy.com/doi/ab … 3.2170_20x
Dissecting the developmental functions of neurosteroids
S. H. Mellon, W. Gong and L. D. Griffin
University of California, San Francisco, CA, USA
The functions of neurosteroids are diverse: they mediate their effects through neurotransmitter receptors such as NMDA and GABAA receptors, and have functions associated with stimulation or inhibition of those receptors. During development, neurosteroids have profound effects on the growth and differentiated function of specific neurons.
Among their many functions, neurosteroids cause growth of specific axons (DHEA), dendrites (DHEAS, progesterone) and regression of neurites (allopregnanolone), modulate myelin production and Schwann cell function (progesterone, allopregnanolone), modulate motorneuron
and cholinergic neuronal function (DHEA), alter expression of neurotransmitter receptor subunits (allopregnanolone).
A mouse model of a human neurodegenerative disease, Niemann-Pick Type C (NP-C), has assisted us in studying the normal function of these neurosteroids during development. In the NP-C mouse model, we find a time-dependent decrease in the expression of neurosteroidogenic enzymes and their activities, which occurs weeks before neurologic phenotypes are evident, and before loss of cerebellar Purkinje cells and cortical neurons.
In vitro cell culture experiments suggest roles for these neurosteroids in survival of specific neuronal populations. Finally, treatment of NP-C mice with the neurosteroid allopregnanolone substantially increases lifespan, delays onset of neurological impairment, and results in increased Purkinje cell number.
Taken together, our data suggest that neurosteroid treatment may be effective in treating some of these neurodegenerative diseases and suggest that appropriately timed synthesis of neurosteroids may be required for normal neural development.