| First Author | Garzón-Niño J | Year | 2017 |
| Journal | Sci Rep | Volume | 7 |
| Pages | 43468 | PubMed ID | 28240305 |
| Mgi Jnum | J:272138 | Mgi Id | MGI:6282681 |
| Doi | 10.1038/srep43468 | Citation | Garzon-Nino J, et al. (2017) Increased PKC activity and altered GSK3beta/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces. Sci Rep 7:43468 |
| abstractText | 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 GSK3beta activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3beta 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. Naive 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 GSK3beta 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. |
