Pitx3 deficient mice as a genetic animal model of co-morbid depressive disorder and parkinsonism

• Published in: Brain research 2014-03, Vol.1552, p.72-81
• Main Authors: Kim, Kyoung-Shim, Kang, Young-Mi, Kang, Young, Park, Tae-Shin, Park, Hye-Yeon, Kim, Yoon-Jung, Han, Baek-Soo, Kim, Chun-Hyung, Lee, Chul-Ho, Ardayfio, Paul A, Han, Pyung-Lim, Jung, Bong-Hyun, Kim, Kwang-Soo
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Anhedonia - drug effects; Animals; Antidepressive Agents - therapeutic use; Biological and medical sciences; Brain - metabolism; Brain - pathology; c-Fos; Comorbidity; Corticosterone - blood; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Depression; Depressive Disorder - drug therapy; Depressive Disorder - genetics; Depressive Disorder - psychology; Dietary Sucrose; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking Behavior; Female; Gene Expression Regulation; Genes, fos; Homeodomain Proteins - genetics; Imipramine - therapeutic use; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mood disorders; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurology; Parkinsonian Disorders - genetics; Parkinsonian Disorders - psychology; Parkinson׳s disease; Proto-Oncogene Proteins c-fos - biosynthesis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Restraint, Physical; Stress; Stress, Psychological - complications; Transcription Factors - deficiency; Transcription Factors - genetics
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2014.01.023

Abstract Approximately 40–50% of all patients with Parkinson׳s disease (PD) show symptoms and signs of depressive disorders, for which neither pathogenic understanding nor rational treatment are available. Using Pit3x-deficient mice, a model for selective nigrostriatal dopaminergic neurodegeneration, we tested depression-related behaviors and acute stress responses to better understand how a nigrostriatal dopaminergic deficit increases the prevalence of depressive disorders in PD patients. Pitx3-deficient mice showed decreased sucrose consumption and preference in the two-bottle free-choice test of anhedonia. Acute restraint stress increased c-Fos (known as a neuronal activity marker) expression levels in various brain regions, including the prefrontal cortex, striatum, nucleus accumbens, and paraventricular nucleus of the hypothalamus (PVN), in both Pitx3+/+ and −/− mice. However, the stress-induced increases in c-Fos levels in the cortex, dorsal striatum, and PVN were significantly greater in Pitx3−/− than +/+ mice, suggesting that signs of depressive disorders in parkinsonism are related to altered stress vulnerability. Based on these results, we propose that Pitx3−/− mice may serve as a useful genetic animal model for co-morbid depressive disorder and parkinsonism.