title: Increased PKC activity and altered GSK3β/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 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.
authors.affiliation: Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, CSIC, Madrid E-28002, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón-Niño
authors.affiliation: Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, CSIC, Madrid E-28002, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, CSIC, Madrid E-28002, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Cortés-Montero
authors.affiliation: Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, CSIC, Madrid E-28002, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015283:Citalopram / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D015398:Signal Transduction; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D014227:Triazines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D015283:Citalopram; D000639:Amitriptyline; D014635:Valproic Acid; D016291:Dizocilpine Maleate; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D018967:Risperidone; D000077213:Lamotrigine