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 Kasper, Ashley E. Smith, Jonathan Hommel, Cheryl F. Lichti, Jai S. Rudra, Marcello D'Ascenzo, Thomas Green & 1 others Fernanda Laezza

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 Nav1.6T1936 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.

Original languageEnglish (US)
Pages (from-to)555-567
Number of pages13
JournalCell Reports
Volume23
Issue number2
DOIs
StatePublished - Apr 10 2018

Fingerprint

Glycogen Synthase Kinase 3
Social Isolation
Neuronal Plasticity
Neurons
Plasticity
Phosphorylation
Rats
Nucleus Accumbens
Electric potential
Reward
Phenotype
Messenger RNA
Peptides

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway. / Scala, Federico; Nenov, Miroslav N.; Crofton, Elizabeth J.; Singh, Aditya K.; Folorunso, Oluwarotimi; Zhang, Yafang; Chesson, Brent C.; Wildburger, Norelle C.; James, Thomas F.; Alshammari, Musaad A.; Alshammari, Tahani K.; Elfrink, Hannah; Grassi, Claudio; Kasper, James; Smith, Ashley E.; Hommel, Jonathan; Lichti, Cheryl F.; Rudra, Jai S.; D'Ascenzo, Marcello; Green, Thomas; Laezza, Fernanda.

In: Cell Reports, Vol. 23, No. 2, 10.04.2018, p. 555-567.

Research output: Contribution to journalArticle

Scala, F, Nenov, MN, Crofton, EJ, Singh, AK, Folorunso, O, Zhang, Y, Chesson, BC, Wildburger, NC, James, TF, Alshammari, MA, Alshammari, TK, Elfrink, H, Grassi, C, Kasper, J, Smith, AE, Hommel, J, Lichti, CF, Rudra, JS, D'Ascenzo, M, Green, T & Laezza, F 2018, 'Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway', Cell Reports, vol. 23, no. 2, pp. 555-567. https://doi.org/10.1016/j.celrep.2018.03.062
Scala, Federico ; Nenov, Miroslav N. ; Crofton, Elizabeth J. ; Singh, Aditya K. ; Folorunso, Oluwarotimi ; Zhang, Yafang ; Chesson, Brent C. ; Wildburger, Norelle C. ; James, Thomas F. ; Alshammari, Musaad A. ; Alshammari, Tahani K. ; Elfrink, Hannah ; Grassi, Claudio ; Kasper, James ; Smith, Ashley E. ; Hommel, Jonathan ; Lichti, Cheryl F. ; Rudra, Jai S. ; D'Ascenzo, Marcello ; Green, Thomas ; Laezza, Fernanda. / Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway. In: Cell Reports. 2018 ; Vol. 23, No. 2. pp. 555-567.
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AU - Zhang, Yafang

AU - Chesson, Brent C.

AU - Wildburger, Norelle C.

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AU - Elfrink, Hannah

AU - Grassi, Claudio

AU - Kasper, James

AU - Smith, Ashley E.

AU - Hommel, Jonathan

AU - Lichti, Cheryl F.

AU - Rudra, Jai S.

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