The neuroactive steroid allopregnanolone up-regulates EAAC1-mediated glutamate uptake in Schwann cells: a neuroprotective mechanism?

The identification of signals regulating Schwann cell proliferation and differentiation under physiological or pathological conditions is of great importance for the development and regeneration of the peripheral nervous system. A role for the neuroactive steroid allopregnanolone (ALLO), which is synthesized de novo in Schwann cells, and classical neurotransmitters in such a control has been recently proposed. Among these must be considered glutamate which is the major excitatory neurotransmitter in the nervous system. Schwann cells express a variety of glutamate receptors and enzymes involved in the glutamate metabolism. We recently observe that Schwann cells also express the high-affinity glutamate transporter EAAC1 in the plasma membrane and in intracellular vesicular compartments. The transporter is functional and its activity is increased by exposure to 10 nM ALLO. The ALLO effect is rapid, does not involve protein neo-synthesis and is prevented by actin depolymerisation. ALLO modulation involves GABA-A receptors and PKC activation, modifies the morphology of cell processes and causes the relocation of the EAAC1 transporter from intracellular stores to the Schwann cell membrane, in actin-rich cell tips. Finally, we provide evidence that the EAAC1 activity mediates the ALLO effect on Schwann cell proliferation. In conclusion, we propose a mechanism of ALLO action on Schwann cells differentiation and proliferation which involves the GABA-A receptor and the glutamate transporter EAAC1. ALLO induces a dynamic remodeling of the actin cytoskeleton and leads to increased surface activity of the glutamate transporter EAAC1 which represents the principal glutamate clearance system in Schwann cells. Understanding the molecular mechanisms through which ALLO and glutamate control Schwann cell differentiation and proliferation may be of interest to develop new therapeutic approaches for treating peripheral neuropathies and promoting regenerative processes