3α,5α-tetrahydroprogesterone (allopregnanolone) and γ-aminobutyric acid: Autocrine/paracrine interactions in the control of neonatal PSA-NCAM+ progenitor proliferation

The earliest identified neonatal neural progenitors are cells that express the polysialylated form of the neural cell adhesion molecule (PSA‐NCAM). One of these progenitors is the early PSA‐NCAM+ progenitor (ePSA‐NCAM+ progenitor; Gago et al. [2003] Mol Cell Neurosci 22:162–178), which corresponds to a multipotential cell with a default differentiation through glial lineages. The ePSA‐NCAM+ progenitor can synthesize the neurosteroid progesterone (PROG) and its reduced metabolite 3α,5α‐tetrahydroprogesterone (3α,5α‐THP, or allopregnanolone; Gago et al. [ 2001] Glia 36:295–308). The latter is a potent positive allosteric modulator of γ‐aminobutyric acid type A (GABAA) receptors. In the present work, we demonstrate that PROG and 3α,5α‐THP both stimulate ePSA‐NCAM+ progenitor proliferation. PROG exerted its mitogenic effect indirectly, through its conversion to 3α,5α‐THP, since it could be abolished by an inhibitor of the 5α‐reductase (L685‐273) and mimicked by 3α,5α‐THP. A dose‐response curve revealed a bell‐shaped effect of 3α,5α‐THP on ePSA‐NCAM+ progenitor proliferation, with greatest stimulation at nanomolar concentrations. The mitogenic effect of 3α,5α‐THP was mediated by GABAA receptors, insofar as it could be blocked by the selective antagonist bicuculline. ePSA‐NCAM+ progenitors indeed expressed mRNAs for GABAA receptor subunits, and GABA enhanced cell proliferation, an effect that was also bicuculline sensitive. Moreover, these cells synthesized GABA, which was involved in a tonic stimulation of their proliferation. These results reveal complex autocrine/paracrine loops in the control of ePSA‐NCAM+ progenitor proliferation, involving both neurosteroid and GABA signaling, and suggest a novel key role for 3α,5α‐THP in the development of the nervous system. © 2004 Wiley‐Liss, Inc.