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

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3 beta (GSK3 beta) 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 GSK3 beta and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3 beta and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3 beta prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3 beta with Nav1.6 and phosphorylation at Nav1.6(T19.36) by GSK3 beta. A GSK3 beta-Nav1.6(T19.36) competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3 beta regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.