Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway
Federico Scala,
Miroslav N. Nenov,
Elizabeth J. Crofton,
Aditya K. Singh,
Oluwarotimi Folorunso,
Yafang Zhang,
Brent C. Chesson,
Norelle C. Wildburger,
Thomas F. James,
Musaad A. Alshammari,
Tahani K. Alshammari,
Hannah Elfrink,
Claudio Grassi,
James M. Kasper,
Ashley E. Smith,
Jonathan D. Hommel,
Cheryl F. Lichti,
Jai S. Rudra,
Marcello D’Ascenzo,
Thomas A. Green,
Fernanda Laezza
Affiliations
Federico Scala
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Biophysics Graduate Program, Institute of Human Physiology, Università Cattolica, Rome, Italy
Miroslav N. Nenov
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
Elizabeth J. Crofton
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Neuroscience Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
Aditya K. Singh
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
Oluwarotimi Folorunso
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
Yafang Zhang
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
Brent C. Chesson
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
Norelle C. Wildburger
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
Thomas F. James
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Neuroscience Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
Musaad A. Alshammari
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA; Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia
Tahani K. Alshammari
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA; Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia
Hannah Elfrink
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Bench Tutorials Program: Scientific Research and Design, The University of Texas Medical Branch, Galveston, TX 77550, USA
Claudio Grassi
Institute of Human Physiology, Università Cattolica, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
James M. Kasper
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
Ashley E. Smith
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA; Cell Biology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
Jonathan D. Hommel
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
Cheryl F. Lichti
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX 77550, USA
Jai S. Rudra
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
Marcello D’Ascenzo
Institute of Human Physiology, Università Cattolica, Rome, Italy
Thomas A. Green
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
Fernanda Laezza
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA; Corresponding author
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. : 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. Keywords: GSK3β, Nav1.6, enriched environment, isolated condition, persistent sodium current, neuronal firing, medium spiny neurons, reward pathway, plasticity
