Are GABA-B receptor ligands of therapeutic interest for cmt1a? New insights for deciphering their mechanisms of action

Despite a large quantity of studies have been focused on the mechanisms controlling and regulating the PMP22 gene expression, the identification of new therapies for the treatment of CMT1A are still a medical need. Presently, there are no standard reliable therapies for CMT1A. Very recent preclinical (by our group) and clinical studies showed that low-dose combination of drugs, including the GABA-B receptor agonist baclofen, are efficient to improve peripheral myelination, proving also able to ameliorate a group of CMT1A patients (Chumakov et al., 2014). In the last decade, several in vitro and in vivo evidences collected in our lab demonstrated that GABA-B activation, decreases proliferation and myelin proteins expression, mainly PMPM22, playing a role in Schwann cells (SCs) differentiation. Subsequent studies on P0-CRE/GABA-B1fl/fl conditional knockout mice (specifically lacking GABA-B1 receptor in SCs) confirmed alterations in the myelination process and revealed that these mice are hyperalgesic. In these mice the morphological and behavioural changes were associated with a downregulation in NRG1 type I levels, concomitantly with an upregulation of ErbB2/ErbB3 and phosphorylated-Erk2 (pErk2), which are key regulator of SCs differentiation towards the pro-myelinating state. However, other receptors, such as the GABA-A receptors, seem to be involved in the SCs biological processes and are supposed to be cross-regulated by GABA-B. Further experiments are in progress in order elucidate the cellular and molecular mechanisms at the base of the GABA-B-mediated control of PMP22.