title: The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation.
abstract: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are widespread environmental contaminants linked to neuropsychological dysfunction in children. 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. In this study, we address the question of whether activation of CREB by NDL PCBs also triggers dendritic spine formation. 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. 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. PCB 95 also induced spine formation via RyR- and miR132-dependent mechanisms in hippocampal slice cultures. 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. 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.
authors.affiliation: Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington 99164, Department of Molecular Biosciences, University of California, Davis, California 95616, and Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Adam
authors.initials: A
authors.lastname: Lesiak
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhu
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Appleyard
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.forename: Gary A
authors.initials: GA
authors.lastname: Wayman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004785:Environmental Pollutants / Q000633:toxicity*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D013131:Spine / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D004785:Environmental Pollutants; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D019837:Ryanodine Receptor Calcium Release Channel; C032904:2,2',3,5',6-pentachlorobiphenyl; D011078:Polychlorinated Biphenyls
keywords: CREB; dendritic spines; developmental neurotoxicity; microRNA; polychlorinated biphenyls; synaptogenesis