Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

Abstract

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder

“…We showed that transgenic mice with neuron-specific expression of mutant Polg1 displayed BD-like phenotypes. 23 The present finding suggests that reduced expression of POLG1, in addition to mutations of POLG1, is relevant to BD.…”

“…Mitochondrial DNA deletion syndrome can accompany BD and depression, 22 and an animal model carrying a mutation in one of these genes (Polg1) showed BD-like behavioral phenotypes. 23 POLG1 (polymerase-g catalytic subunit), WFS1 (Wolfram syndrome 1), POLG2 (polymerase-g accessory subunit), SLC25A4 (ANT1, adenine nucleotide translocator 1) and Twinkle (C10orf2; mitochondrial DNA helicase).…”

“…These values are, however, comparable with other established screening tests. For example, the sensitivity and specificity is 34.9% and 63.1%, respectively, for prostate-specific antigen in prostate cancer, 37 23.9% and 93.8%, respectively, for fecal occult-blood testing in colorectal cancer 38 and 64.3% and 91.4%, respectively, for a-fetoprotein in hepatocellular carcinoma. 39 In this study, we selected a representative gene from each study.…”

Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

“…Notably, mitochondrial dysfunction is increasingly being noted in schizophrenia, bipolar disorder and other mood disorders, based on the expression pattern of mitochondria related genes, as well as on morphological and biochemical analysis of mitochondrial function in patients [41][42][43] and animal models. 44 …”

Convergent functional genomics of psychiatric disorders

“…That work was subsequently extended to look at the gene expression changes in blood from the animals on the different treatments, as a way of identifying brain-blood biomarkers [Le-Niculescu et al, 2009b]. Niculescu et al, 2008Niculescu et al, , 2011b Nile grass rat [Ashkenazy-Frolinger et al, 2010] Methamphetamine [Niculescu et al, 2000;Macedo et al, 2013] Learned helplessness [Mingmalairak et al, 2010] CLOCK [Roybal et al, 2007;Mukherjee et al, 2010;Arey et al, 2013] Flinders Sensitive Line (FSL) rats [Malkesman and Weller, 2009] Methamphetamine/valproate [Ogden et al, 2004] Isolation housing [Le-Niculescu et al, 2008;Niwa et al, 2013] CTNNB1 [Gould et al, 2008] Wistar Kyoto (WKY) rats [Will et al, 2003;Malkesman and Weller, 2009] Amphetamine-chlordiazepoxide [Kelly et al, 2009] Forced swim test [Le-Niculescu et al, 2008] POLG [Kasahara et al, 2006;Kubota et al, 2010] Madison (MSN) [Saul et al, 2012] Lithium [Gould et al, 2007;Johnson et al, 2009;Kovacsics and Gould, 2010] Tail suspension test [Le-Niculescu et al, 2008] HINT1 [Barbier and Wang, 2009] Other mood stabilizers: Lamotrigene [Li et al, 2010], Topiramate [Bourin et al, 2009] Restraint stress [Johnson et al, 2009;Koo et al, 2010] GRIN2A [Taniguchi et al, 2009] Ouabain [Herman et al, 2007] Shock-induced aggression …”