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Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or
Javier Garzón-Niño1, María Rodríguez-Muñoz1, Elsa Cortés-Montero1
1Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, CSIC, Madrid E-28002, Spain.
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 GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3β 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 GSK3β 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.
Insights
Mice lacking histidine triad nucleotide-binding protein 1 (HINT1) show bipolar disorder-like behaviors. Targeting protein kinase C (PKC) and N-methyl-D-aspartate receptors (NMDARs) may offer new treatments for this mental disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Histidine triad nucleotide-binding protein 1 (HINT1) deletion in mice leads to manic-like symptoms that transition to depressive-like behaviors under stress.
- HINT1-/- mice exhibit altered molecular pathways, including increased PKC, PKA, and GSK3β activities, and modified NMDAR/AMPAR and NR2B/NR2A subunit ratios.
Purpose of the Study:
- To investigate the behavioral and molecular mechanisms underlying HINT1-/- mouse model of bipolar disorder.
- To explore the efficacy of different pharmacological interventions in modulating these behaviors.
Main Methods:
- Behavioral analysis of HINT1-/- mice under various stress paradigms.
- Molecular and electrophysiological assessments of key signaling pathways and receptor subunits.
- Pharmacological interventions targeting GSK3β, PKC, and NMDARs.
Main Results:
- GSK3β inhibitors and valproate reduced manic-like symptoms, while PKC inhibition, lamotrigine, and risperidone induced NMDAR-mediated depressive-like behaviors.
- Stressed HINT1-/- mice exhibited persistent depressive-like behaviors, and certain antidepressants precipitated manic-like behaviors.
- NMDAR antagonism prevented behavioral switching in response to stress, and PKC was found to support manic-like symptoms in these mice.
Conclusions:
- HINT1-/- mice serve as a valuable model for studying human bipolar disorder (BPD).
- PKC signaling, GSK3β activity, and NMDAR subunit composition are critical in regulating the behavioral phenotype.
- This model may aid in identifying novel therapeutic targets and drugs for BPD.
