Protein-protein interactions (PPI) offer unexploited opportunities for CNS drug discovery and neurochemical probe development. Here, we present ZL181, a novel peptidomimetic targeting the PPI interface of the voltage-gated Na channel Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). ZL181 binds to FGF14 and inhibits its interaction with the Nav1.6 channel C-tail. In HEK-Nav1.6 expressing cells, ZL181 acts synergistically with FGF14 to suppress Nav1.6 current density and to slow kinetics of fast inactivation, but antagonizes FGF14 modulation of steady-state inactivation that is regulated by the N-terminal tail of the protein. In medium spiny neurons in the nucleus accumbens, ZL181 suppresses excitability by a mechanism that is dependent upon expression of FGF14 and is consistent with a state-dependent inhibition of FGF14. Overall, ZL181 and derivatives could lay the ground for developing allosteric modulators of Nav channels that are of interest for a broad range of CNS disorders.

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer's disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

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 by GSK3β. A GSK3β-Nav1.6 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.