Increased PKC activity and altered GSK3?/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces.

ABSTRACT: Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1^-/- mice exhibit increased PKC, PKA, and GSK3? activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3? inhibitors and valproate directly attenuated the expression of the manic-like symptoms, whereas PKC inhibition, lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors that counterbalanced the preexisting manic-like symptoms. Naïve HINT1^-/- mice exposed to stressful paradigms rapidly manifested depressive-like behaviors in subsequent stressful situations, a capacity that persisted for a couple of weeks thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 precipitated manic-like behaviors in stressed HINT1^-/- mice. Notably, the antagonism of NMDARs prevented HINT1^-/- mice from alternating behaviors in response to stress. A comparison with "manic" Black Swiss mice indicated that in HINT1^-/- mice, PKC supports manic-like symptoms and reduces the expression of depressive-like behaviors via activation of GSK3? and regulation of NR2B-enriched NMDARs. HINT1^-/- mice represent a suitable model for studying human BPD and may facilitate the identification of novel targets and drugs to treat this mental disorder.

SUBMITTER: Garzon-Nino J 

PROVIDER: S-EPMC5327482 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature