Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABAA receptors in Wfs1-deficient mice

Raud, Sirli; Sütt, Silva; Luuk, Hendrik; Plaas, Mario; Innos, Jürgen; Kõks, Sulev; Vasar, Eero

doi:10.1016/j.neulet.2009.05.054

Cited by 41 publications

(25 citation statements)

References 20 publications

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“…Our cohort also had notable depression and anxiety, similar to findings in advanced WFS [95] and anxiety behaviors found in animal models of WFS (wfs1-deficient mice) [96]. While cerebellar dysfunction has also been associated with altered mood [97], we cannot currently distinguish whether these symptoms are a reaction to living with a chronic, degenerative condition or if they are part of the disease process itself.…”

Section: Discussionsupporting

confidence: 63%

Early Brain Vulnerability in Wolfram Syndrome

et al. 2012

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Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

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Section: Discussionsupporting

confidence: 63%

Early Brain Vulnerability in Wolfram Syndrome

et al. 2012

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“…The analysis of qRT-PCR data was performed as described previously by Raud et al (2009). Briefly, qRT-PCR data in figures is presented on a linear scale, calculated as 2 −Δ CT , where Δ CT is the difference in cycle threshold (CT) between the target gene ( Lsamp ) and housekeeper gene Hprt-1 (VIC-MGB).…”

Section: Methodsmentioning

confidence: 99%

Gene expression patterns and environmental enrichment-induced effects in the hippocampi of mice suggest importance of Lsamp in plasticity

et al. 2015

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Limbic system associated membrane protein (Lsamp) gene is involved in behavioral adaptation in social and anxiogenic environments and has been associated with a broad spectrum of psychiatric diseases. Here we studied the activity of alternative promoters of Lsamp gene in mice in three rearing conditions (standard housing, environmental enrichment and social isolation) and in two different genetic backgrounds (129S6/SvEv and C57BL/6). Isolation had no effect on the expression levels of Lsamp. Environmental enrichment elevated the expression levels of Lsamp 1b transcript specifically in the hippocampus in B6 mice, and the same tendency existed across both mouse lines and both transcripts. Furthermore, we showed that the density of cells exhibiting 1b promoter activity is remarkably higher in the subgranular zone of the dentate gyrus in the hippocampal formation which is a specific area of enrichment-induced neurogenesis in adult rodents. On the contrary to 1b, 1a promoter is selectively active in the pyramidal and granule cell layers. We provide evidence that Lsamp modulates enrichment-induced activation of Bdnf as the enrichment-induced elevation of Bdnf in the hippocampus is significantly diminished in Lsamp-deficient mice; furthermore, a significant correlation was found between the expression levels of Lsamp and Bdnf transcripts in the hippocampus and frontal cortex. Significant strain differences in Lsamp expression were detected in the hippocampus, frontal cortex and thalamus that could be related to the different behavioral phenotype of B6 and 129Sv mice. Our data provides further evidence that LSAMP is implicated in the hippocampal connectivity and plasticity thereby modulating adaptability in changing environments.

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“…In addition, the Wfs1 KO animals are emotionally and motivationally deviated, and although not well documented, they may express some cognitive deficit as well. In particular, the mental deficiency of the Wfs1 KO mice seems to be associated with stressful events and situations [13,18].…”

Section: Introductionmentioning

confidence: 99%

Impaired striatal dopamine output of homozygous Wfs1 mutant mice in response to [K+] challenge

et al. 2010

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Loss of function of the Wfs1 gene causes Wolfram syndrome, a rare multisystem degenerative disorder. Mutant mice with targeted Wfs1 gene disruption (Wfs1 KO) display morphological and behavioral impairments that are not well understood. The present study aimed to investigate the striatal dopamine output of wild-type, heterozygous, and homozygous Wfs1 null-mutant mice using in vivo microdialysis technique. The baseline dopamine output in striatum was similar in all three animal groups. The application of 100 mM [K+]-rich modified Ringer solution caused in homozygous Wfs1 mutant mice an increase of dopamine output by 400%, while in wild-type and heterozygous animals, the increase of the dopamine output yielded up to 1,200%. In sum, the homozygous Wfs1 mutant mice (AUC₀₋₃ = 0.212 nM/μl h) show significantly decreased striatal dopamine output in response to high-concentration [K+] challenge as compared with wild-type or heterozygous Wfs1 mutant conspecifics (AUC₀₋₃ = 0.427 and 0.505 nM/μl h, respectively). This could explain at least some of the behavioral alterations in Wfs1 mutant mice.

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Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABAA receptors in Wfs1-deficient mice

Cited by 41 publications

References 20 publications

Early Brain Vulnerability in Wolfram Syndrome

Early Brain Vulnerability in Wolfram Syndrome

Gene expression patterns and environmental enrichment-induced effects in the hippocampi of mice suggest importance of Lsamp in plasticity

Impaired striatal dopamine output of homozygous Wfs1 mutant mice in response to [K+] challenge

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