Synthesis of Gaba in Schwann cells is induced by the neuroactive steroid allopregnanolone

Recently we hypothesized that, in the PNS, the Schwann cells are the primary target for GABA’s action, as shown by the presence of mRNAs coding for a variety of GABA-A and GABA-B receptor subunits (Magnaghi, Curr. Neuropharmacol. 2007). Allopregnanolone (ALLO), a reduced metabolite of progesterone, modulates GABA-A receptor in Schwann cells and increases mRNA and protein levels of PMP22 (Magnaghi, Brain Res Rev. 2001). This observation is supported by the evidence that muscimol (a selective GABA-A agonist) similarly enhances PMP22 mRNA levels, whereas bicuculline (a specific GABA-A antagonist) counteracts such increase (Magnaghi, Brain Res Rev. 2001). Therefore, the expression of PMP22 in Schwann cells seems to be under control of GABA-A receptor. In addition, ALLO induces a robust stimulation of the mRNAs coding for some GABA-B receptor subunits. These effects are partially mimicked by muscimol, suggesting that ALLO controls GABA-B receptor expression through GABA-A mediated mechanism (Magnaghi, J Mol. Neurosci 2006). However, the general mechanism downstream ALLO activation of GABA-A is still elusive. Consequently, we aimed at elucidating ALLO’s-mediated mechanism(s) in Schwann cells, and its putative effects on GABA synthesis. By means of different approaches we demonstrated the presence of glutamic acid decarboxylase of 67 kDa (GAD67) in Schwann cells; additionally we demonstrated that GABA is synthesized and localized in Schwann cells. Finally, we suggested that PKA pathway, through enhanced cAMP levels and CREB phosphorylation is the intracellular signalling pathway responsible for such an allosteric action of ALLO at GABA-A receptor in Schwann cells. The knowledge of these mechanisms, therefore, might be important to establish new putative strategies to treat peripheral neuropathies.