Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway
| Autor: | Musaad A. Alshammari, Cheryl F. Lichti, Aditya K. Singh, Marcello D'Ascenzo, Miroslav N. Nenov, Tahani K. Alshammari, Brent C. Chesson, Jonathan D. Hommel, Ashley E. Smith, Elizabeth J. Crofton, Jai S. Rudra, Thomas F. James, Thomas A. Green, James M. Kasper, Claudio Grassi, Norelle C. Wildburger, Hannah Elfrink, Oluwarotimi Folorunso, Yafang Zhang, Federico Scala, Fernanda Laezza |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Phosphopeptides 0301 basic medicine Patch-Clamp Techniques Settore BIO/09 - FISIOLOGIA Nucleus accumbens Biology Medium spiny neuron Article General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Physical Conditioning Animal Neuroplasticity Animals Humans RNA Small Interfering lcsh:QH301-705.5 Evoked Potentials GSK3B Neurons Environmental enrichment Glycogen Synthase Kinase 3 beta Neuronal Plasticity HEK 293 cells Phenotype Rats Cell biology neuropsychiatric disorders HEK293 Cells 030104 developmental biology lcsh:Biology (General) Social Isolation NAV1.6 Voltage-Gated Sodium Channel SCN8A mRNA GSK3b Phosphorylation RNA Interference Transcriptome 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Cell reports Cell Reports, Vol 23, Iss 2, Pp 555-567 (2018) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions—models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. In Brief Scala et al. show how vulnerability to reward-related behaviors associates with maladaptive plasticity of medium spiny neurons through phosphorylation of the voltage-gated Na+ channel Nav1.6 by the enzyme GSK3β. |
| Databáze: | OpenAIRE |
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