GABAB receptor in oligodendrocytes and its therapeutic potential against demyelinating diseases

Abstract

In this doctoral thesis, we have identified the differentiation mechanisms influenced by GABAB receptor (GABABR) in oligodendrocytes and we have examined its potential for (re)myelination. First, we evaluated the consequences of GABABR modulation in cultured oligodendrocyte progenitor cells (OPCs), using GABABR agonist baclofen or antagonist CGP. Baclofen promoted OPC differentiation and myelination in vitro, whereas treatment with CGP reverted this effect. In order to identify the signaling pathways triggered by GABABR activation, we performed immunoblot analysis to determine the phosphorylation state of relevant mediators of OPC differentiation. Indeed, baclofen treatment regulated the activation of PKC, CREB, p38, Akt and Src. Considering the robust effect mediated by baclofen in cultured oligodendrocytes, we next tested its potential in mouse models of demyelination. Baclofen exerted a protective effect following lysolecithin-induced spinal cord demyelination, promoting OPC differentiation and the remyelination rate within the lesions. Similarly, baclofen ameliorated the progression of experimental autoimmune encephalomyelitis (EAE) and enhanced OPC differentiation in EAE lesions. We also evaluated the consequences of GABAB1 deletion in OPCs, inducing EAE in knockout mice lacking the receptor subunit, and observed that symptom severity was reduced in these mice in the acute phase of the EAE. Single nuclei RNA sequencing analysis in these mice revealed several differentially expressed genes, including upregulation of immune genes in oligodendrocytes following GABAB1 ablation. Finally, we tested the effect of baclofen in physiological conditions during rat development myelination. No relevant differences were found following baclofen treatment in oligodendrocytes or in myelination levels, but baclofen significantly reduced the density of interneurons in the cortex of developing rats. Interestingly, earlier baclofen administration did enhance OPC differentiation in the cortex. Taken together, these results provide evidence about the relevance of GABABR in OPC differentiation and identify its agonist baclofen as a promising candidate for remyelinating therapies in multiple sclerosis.