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. 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 language | English (US) |
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Pages (from-to) | 555-567 |
Number of pages | 13 |
Journal | Cell Reports |
Volume | 23 |
Issue number | 2 |
DOIs | |
State | Published - Apr 10 2018 |
Keywords
- GSK3β
- Nav1.6
- enriched environment
- isolated condition
- medium spiny neurons
- neuronal firing
- persistent sodium current
- plasticity
- reward pathway
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology