NEUROINFLAMMATION AND DEFECTIVE MYELINATION IN POLYMICROGYRIA

Polymicrogyria (PMG) is a condition characterized by abnormal prenatal brain development and excessive number of ectopic small gyri in the cerebral cortex. PMG patients present an excessive number of abnormally small gyri separated by shallow sulci, associated with fusion of the overlying molecular layer of the cerebral cortex. The topographic distribution of PMG may be focal, multifocal or diffuse; unilateral or bilateral; symmetric or asymmetric. Clinical manifestations have a large spectrum, ranging from isolated selective impairment of cognitive functions to severe encephalopathy and intractable epilepsy. The severity of neurological manifestations and the age at presentation are in part influenced by the extent and localization of the cortical malformations but may also depend on its specific aetiology. The pathogenesis is still poorly understood, several causative gene mutations have been recently found, but also other causes has been identified (prenatal infections, ipoxia). Experimentally, the mouse model of polymicrogyria (PMG) displays the formation of ectopic microgyri in the mouse cortex, enhanced excitatory and inhibitory synaptic transmission accompanied by increased connectivity in the paramicrogyral cortex and higher susceptibility to epilepsy in vitro. Besides the alteration in the cortical layering, the molecular, morphological and behavioural analysis of PMG mice reveal a significant astrogliosis and microglial activation, indicating the occurrence of an inflammatory process. In addition, a diffuse cortical hypomyelination is evident in brain slices stained for myelin basic protein (MBP). Furthermore, PMG mice displayed altered EEG profile and defective motor skills such as reduced brawn. All these features make PMG model suitable for the study of the pathology and to investigate possible therapeutic approaches. Here we found that transplantation of human neural stem cells (hNSCs), which has been demonstrated to exert positive effects on inherited or acquired myelination disorders and to dampen brain inflammation, plays a beneficial effect on the pathological condition of PMG ameliorating the myelination defect by promoting oligodendrocyte precursors proliferation and remodelling of myelin fibres. Our data also show that hNSC transplantation restores normal EEG brain activity and improves motor performances. Moreover, we tried a pharmacological blockade of IL-1R activation by the IL-1R antagonist: anakinra. We found that this treatment leads to a significant improvement of EEG and motor skills in adult PMG mice thus suggesting a possible role of inflammation at the root of the pathology and identifying a therapeutic time window for the treatment.