Connexin expression in CNS: Pathological significance and Lithium-mediated neuroprotection

Abstract

The communication between cells in physiological and pathological conditions is mediated by clusters of intercellular channels called Gap Junctions which are composed by transmembrane proteins family called connexin (Cx). The expression and function of connexins in several pathological conditions is a topic of great interest and with unknown aspects to be investigated further. This is the theme of my thesis, which investigates the expression of connexins in different models of pathology of the CNS and also the possibility to modulate the response by neuroprotective agents like Lithium Chloride. Three different studies were performed: i) Dynamic Expression of Cx47 in Mouse Brain Development and in the Cuprizone Model of Myelin Plasticity: the study shows the dynamic expression of connexin47 (Cx47) in oligodendrocytes and myelin of mice, either in myelinogenesis occurring in early development or in an ex- perimental model of new-myelinogenesis of adult mice. ii) Expression of Connexin57 in mouse development and harmaline-tremor model: the up-regulation of the Cx57 transcripts reported in this model suggested a possible involvement of Cx57 in the electrotonic coupling of the cerebellar system. iii) Expression oattern of connexins and pannexins in primary human astroglial cell cultures exposed to glutamate or lipolysaccharide: the effects of the administration of LPS (1,10, 100 µg/ml) or glutamate (10, 50, 100 µM) for different time intervals (12, 24 and 48 h) were tested in human astrocytes. Four parameters were compared: cytological modification, cell viability, level of ROS and GSH, the level of mRNA of connexins (Cxs): Cx26, Cx30, Cx43 and pannexins (Panx): Panx 1 and Panx2. Main findings were:1) the stressors (LPS and glutamate) increased the mRNA level of Cx26 and Cx30, while Cx43, Panx1 and Panx2 were not significantly modified; 2) the level of Cx26 and Cx30 increased strongly at lower doses of stressors while increasing the doses of the stressors, the increment of Cx26 and Cx30 progressively lowered. Conversely, the level of the ROS increased with the doses of the stressors; 3) an inversed relation occurred between level of Cxs (Cx26 and Cx30) and grade of injury of the cells (as proved by astrocytosis and by MTT test).

Since there will be a close correlation between neurodegenerative disease and expression of connexin, the last step of the work concerns the possibility to control the expression of connexins by the administration of a neuroprotective agent such as lithium.