Behavioral and gene expression analyses of Wfs1 knockout mice as a possible animal model of mood disorder
Introduction
Wolfram disease (Online Mendelian Inheritance in Man [OMIM] 222300) is a rare autosomal recessive neurodegenerative disorder characterized by early-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus, and deafness (Domenech et al., 2006); WfS1/wolframin has been identified as the causative gene (Strom et al., 1998, Inoue et al., 1998). Approximately, 60% of the patients with Wolfram disease have mental symptoms, such as severe depression, psychosis, impulsivity, and aggression (Swift et al., 1990). More importantly, carriers of WfS1 mutations, who are not affected with Wolfram disease, have a 26-fold higher likelihood of psychiatric hospitalization mainly due to depression (Swift and Swift, 2000). The WfS1 gene locates at 4p16.1 (Strom et al., 1998, Inoue et al., 1998), a replicated linkage locus of bipolar disorder (Ewald et al., 1998, Ewald et al., 2002, Detera-Wadleigh et al., 1999). Some studies showed that bipolar disorder with psychosis (Als et al., 2004, Cheng et al., 2006) or suicidal behavior (Cheng et al., 2006) is linked with this locus. These lines of evidence suggested the possible role of WfS1 mutations in the pathophysiology of bipolar disorder and related phenotypes.
To date, mutation screening of the WfS1 gene has been reported in 84 patients with bipolar disorder, 54 with major depression, 119 with schizophrenia, 100 suicide victims, 3 with schizoaffective disorder, and several other patients with other psychiatric diagnoses (Ohtsuki et al., 2000, Martorell et al., 2003, Torres et al., 2001, Crawford et al., 2002, Evans et al., 2000). However, none of these patients had mutations causing Worfram disease.
Despite the fact that WfS1 mutations may not be a frequent cause of mental disorders, the mechanism underlying how WfS1 mutations lead to mental symptoms in patients with Wolfram disease will shed light on the pathophysiology of mood disorders. Mice lacking the Wfs1 gene might be useful as a genetic animal model of mood disorders.
The symptoms of Wolfram disease resemble those of mitochondrial diseases and, indeed, initial studies suggested mitochondrial dysfunction in Wolfram disease based on mitochondrial DNA (mtDNA) deletions found in patients (Rotig et al., 1993). However, the protein coded by WfS1 was found to be localized in endoplasmic reticulum (ER) (Takeda et al., 2001, Philbrook et al., 2005). WfS1 expression was induced by ER stress (Fonseca et al., 2005) or XBP1 overexpression (Kakiuchi et al., 2006), and disruption of Wfs1 caused a dysfunctional ER stress response (Fonseca et al., 2005, Riggs et al., 2005, Yamada et al., 2006). Recent studies have provided insight into the function of WfS1 protein; WfS1 induces cation channel activity on ER membranes (Osman et al., 2003) and regulates calcium levels in ER (Takei et al., 2006). It also plays a role in stimulus-secretion coupling for insulin exocytosis in pancreatic β cells (Ishihara et al., 2004). Disruption of Wfs1 increased vulnerability to cell death in the knockout (KO) mice (Ishihara et al., 2004, Philbrook et al., 2005, Riggs et al., 2005, Yamada et al., 2006). In the rat brain, WfS1 was distributed predominantly in neurons of the so-called limbic system (Takeda et al., 2001). WfS1 mutations could lead to loss of WfS1-expressing neurons in particular brain regions of patients with Wolfram disease, which may underlie progression of mental symptoms.
In this study, we performed behavioral analysis of Wfs1 KO mice to characterize their behavioral abnormality. We previously developed neuron-specific mutant polymerase γ-transgenic mice (mPolg Tg mice) based on a mitochondrial dysfunction hypothesis of bipolar disorder (Kato and Kato, 2000) and demonstrated that these mice had bipolar disorder-like phenotypes, such as altered circadian rhythm and periodic fluctuation of wheel-running activity (Kasahara et al., 2006). Whether or not the Wfs1 KO mice show such wheel-running activity was examined. A behavioral test battery was also conducted to search for other behavioral phenotypes. Distribution of Wfs1 in the brain was examined to search for the neural basis of behavioral alteration. In addition, gene expression analysis was performed to search for the molecular basis of behavioral phenotypes of Wfs1 KO mice.
Section snippets
Generation of Wfs1 KO mice
The methods for the generation of Wfs1 KO mice have been described elsewhere (Ishihara et al., 2004). In brief, a neomycin-resistance gene was inserted into exon 2 of the Wfs1 gene in the targeting vector. The targeting vector was injected into 129Sv embryonic stem (ES) cells, and the ES cells with homologous recombination were obtained. By crossing the chimeric mice with C57BL/6J (B6) mice, Wfs1 heterozygous KO mice were obtained. Genotyping was performed as previously described (Ishihara et
Wheel-running activity
To assess whether or not the Wfs1 KO mice show bipolar disorder-like behavioral phenotypes, wheel-running activity of the Wfs1 KO mice and WT littermates was recorded for a period up to 2 months. The levels of wheel-running activity and the circadian rhythm were assessed using male mice that were 34 weeks old at the initiation of this analysis (KO, n = 11; WT, n = 9). Average wheel-running activity per day of Wfs1 KO mice during 28 days under the L-D condition did not differ from that of WT
Behavioral analyses
We recently reported that mPolg Tg mice show bipolar disorder-like behavioral phenotypes, such as altered circadian rhythm in both males and females and periodic fluctuation of wheel-running activity in females (Kasahara et al., 2006). Based on previous reports suggesting that patients with Wolfram disease are frequently affected with depression or bipolar disorder, we speculated that the Wfs1 KO mice might also show these bipolar disorder-like phenotypes, which were seen in the mPolg Tg mice.
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