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

doi:10.1016/j.celrep.2018.03.062

Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway

Cell Rep. 2018 Apr 10;23(2):555-567. doi: 10.1016/j.celrep.2018.03.062.

Authors

Federico Scala¹, Miroslav N Nenov², Elizabeth J Crofton³, Aditya K Singh², Oluwarotimi Folorunso², Yafang Zhang⁴, Brent C Chesson⁴, Norelle C Wildburger², Thomas F James³, Musaad A Alshammari⁵, Tahani K Alshammari⁵, Hannah Elfrink⁶, Claudio Grassi⁷, James M Kasper⁸, Ashley E Smith⁹, Jonathan D Hommel⁸, Cheryl F Lichti¹⁰, Jai S Rudra², Marcello D'Ascenzo¹¹, Thomas A Green⁸, Fernanda Laezza¹²

Affiliations

¹ 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.
² Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Institute of Human Physiology, Università Cattolica, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ Institute of Human Physiology, Università Cattolica, Rome, Italy.
¹² 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. Electronic address: felaezza@utmb.edu.

Abstract

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 Nav1.6^T1936 by GSK3β. A GSK3β-Nav1.6^T1936 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.

Keywords: GSK3β; Nav1.6; enriched environment; isolated condition; medium spiny neurons; neuronal firing; persistent sodium current; plasticity; reward pathway.

MeSH terms

Animals
Evoked Potentials
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
Glycogen Synthase Kinase 3 beta / genetics
Glycogen Synthase Kinase 3 beta / metabolism*
HEK293 Cells
Humans
Male
NAV1.6 Voltage-Gated Sodium Channel / chemistry
NAV1.6 Voltage-Gated Sodium Channel / genetics
NAV1.6 Voltage-Gated Sodium Channel / metabolism
Neuronal Plasticity / physiology*
Neurons / metabolism*
Patch-Clamp Techniques
Phosphopeptides / analysis
Physical Conditioning, Animal*
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism
Rats
Rats, Sprague-Dawley
Social Isolation*
Transcriptome

Substances

NAV1.6 Voltage-Gated Sodium Channel
Phosphopeptides
RNA, Small Interfering
Glycogen Synthase Kinase 3 beta

Abstract

MeSH terms

Substances

Grants and funding