Elsevier

Neuroscience Research

Volume 61, Issue 2, June 2008, Pages 143-158
Neuroscience Research

Behavioral and gene expression analyses of Wfs1 knockout mice as a possible animal model of mood disorder

https://doi.org/10.1016/j.neures.2008.02.002Get rights and content

Abstract

Wolfram disease is a rare genetic disorder frequently accompanying depression and psychosis. Non-symptomatic mutation carriers also have higher rates of depression and suicide. Because WfS1, the causative gene of Wolfram disease, is located at 4p16, a linkage locus for bipolar disorder, mutations of WfS1 were suggested to be involved in the pathophysiology of bipolar disorder. In this study, we performed behavioral and gene expression analyses of Wfs1 knockout mice to assess the validity as an animal model of mood disorder. In addition, the distribution of Wfs1 protein was examined in mouse brain. Wfs1 knockout mice did not show abnormalities in circadian rhythm and periodic fluctuation of wheel-running activity. Behavioral analysis showed that Wfs1 knockout mice had retardation in emotionally triggered behavior, decreased social interaction, and altered behavioral despair depending on experimental conditions. Wfs1-like immunoreactivity in mouse brain showed a similar distribution pattern to that in rats, including several nuclei potentially relevant to the symptoms of mood disorders. Gene expression analysis showed down-regulation of Cdc42ep5 and Rnd1, both of which are related to Rho GTPase, which plays a role in dendrite development. These findings may be relevant to the mood disorder observed in patients with Wolfram disease.

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.

References (39)

  • R. Threadgill et al.

    Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42

    Neuron

    (1997)
  • T.D. Als et al.

    Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands

    Mol. Psychiatry

    (2004)
  • A. Cano et al.

    Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome

    Am. J. Med. Genet. A

    (2007)
  • R. Cheng et al.

    Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder

    Mol. Psychiatry

    (2006)
  • J. Crawford et al.

    Is there a relationship between Wolfram syndrome carrier status and suicide?

    Am. J. Med. Genet.

    (2002)
  • J.N. Crawley

    What's Wrong with My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice

    (2007)
  • S.D. Detera-Wadleigh et al.

    A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2

    Proc. Natl. Acad. Sci. U.S.A.

    (1999)
  • S.D. Detera-Wadleigh et al.

    Sequence variation in DOCK9 and heterogeneity in bipolar disorder

    Psychiatry Genet.

    (2007)
  • E. Domenech et al.

    Wolfram/DIDMOAD syndrome, a heterogenic and molecularly complex neurodegenerative disease

    Pediatr. Endocrinol. Rev.

    (2006)
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