Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus.
Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Kasahara
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Takata
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Kato
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Kubota-Sakashita
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Sawada
Department of Pathology, Brain Research Institute, Niigata University, Niigata-shi, Niigata, Japan.
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Kakita
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi, Japan.
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Mizukami
Department of Neurology, Osaka Red Cross Hospital, Osaka-shi, Osaka, Japan.
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Kaneda
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi, Japan.
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Ozawa
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
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Kato
D000818:Animals; D015897:Comorbidity; D003345:Corticosterone / Q000032:analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D003866:Depressive Disorder / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008822:Mice, Transgenic; D020644:Midline Thalamic Nuclei / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications / Q000378:metabolism / Q000473:pathology
D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D003345:Corticosterone