Role of Myelin-associated glycoprotein in cerebellar neurodevelopment: it?s possible impact on pathogenesis of Autistic Sprectrum Disorders

MATTALLONI, MARA S.; ANABELA PALANDRI; CRISTIAN BACAGLIO; PABLO LOPEZ

Workshop; The role of glial cells in health and disease of the Nervous System: Clinical and Basic Science walking together; 2017

Ibro

We recently reported that Myelin-associated glycoprotein (MAG), a minor constituent ofthe nervous system expressed by oligodendrocytes, modulates early postnatal apoptosisof motoneurons by engaging Nogo receptors (NgRs) via activation of RhoA/ROCKsignaling pathways. Based on this background, is interesting study whether the protectiverole of MAG is restricted to MNs or could be generalized to other neuronal populations. Wenow extended these studies to the developing cerebellum, which in rodents occurs mostlyearly after birth. Early postnatal treatment of wild type mice (P0-P3) with a functionblockingantibody anti-MAG mAb (mAb 513) induced alterations of cerebellumdevelopment that mimics the findings observed in MAG-null mice. Morphometric analysisof cerebellum from both group identified alterations of cerebellar developmentcharacterized by an increased number of Purkinje and Granule neurons. Treatment with acell proliferation dye at postnatal P4-5 confirmed delayed proliferation of CGN meanwhileFluoro Jade C staining identified increased neurodegeneration restricted to this cellpopulation. Similar findings were observed in mice lacking NgRs (triple NgR-null),highlighting the functional role of these receptors. Recently anatomical, clinical, andneuroimaging studies strongly suggest that the cerebellum supports cognitive functions,including language, social interaction and executive functions, as well as affectiveregulation and has emerged as one of the key brain regions affected in autism (ASD); andis intimately linked to behavioral symptoms seen in the pathology. Therefore we furtheranalyzed the possible contribution of MAG to the pathogenesis of ASDs by studying socialinteraction and ultravocalizations in pups treated with mAb 513 early after birth. Our resultsshow that blocking of MAG and MAG-null mice resembles phenotypic behaviorsassociated with ASDs. Altogether our data corroborates the role of MAG as a criticalmodulator of postnatal cerebellar development and at the same time suggest that could beconsidered as a novel factor contributing to the pathogenesis of autism.