![]() Dendritic spines are exquisitely responsive to external cues, especially during development. Abnormalities in the density or shape of dendritic spines are associated with many neurodevelopmental disorders, including mental retardation, autism spectrum disorders (ASDs), and schizophrenia ( Fukuda et al., 2005 Penzes et al., 2008 Bourgeron, 2009 Garey, 2010 Svitkina et al., 2010). In light of recent evidence implicating miR132 dysregulation in Rett syndrome and schizophrenia, these findings identify NDL PCBs as potential environmental risk factors for neurodevelopmental disorders.ĭendritic spines are the primary site of excitatory synaptic input, and their formation is critical for normal neural function ( Segal, 2005). These data demonstrate a novel mechanism of PCB developmental neurotoxicity whereby RyR sensitization modulates spine formation and synaptogenesis via CREB-mediated miR132 upregulation, which in turn suppresses the translation of p250GAP, a negative regulator of synaptogenesis. ![]() PCB 95 also induced spine formation via RyR- and miR132-dependent mechanisms in hippocampal slice cultures. Inhibition of RyR, CREB, or miR132 as well as expression of a mutant p250GAP cDNA construct that is not suppressed by miR132 blocked PCB 95 effects on spines and miniature EPSCs. Nanomolar concentrations of PCB 95, a NDL congener with potent RyR activity, significantly increased spine density and the frequency of miniature EPSCs in primary dissociated rat hippocampal cultures coincident with upregulation of miR132. In this study, we address the question of whether activation of CREB by NDL PCBs also triggers dendritic spine formation. NDL PCBs increase spontaneous Ca 2+ oscillations in neurons by stabilizing ryanodine receptor (RyR) calcium release channels in the open configuration, which results in CREB-dependent dendritic outgrowth. Non–dioxin-like (NDL) polychlorinated biphenyls (PCBs) are widespread environmental contaminants linked to neuropsychological dysfunction in children.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |