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A mutation causing increased KATP channel activity leads to reduced anxiety in mice.

ABSTRACT: Activating mutations in the Kir6.2 (KCNJ11) subunit of the ATP-sensitive potassium channel cause neonatal diabetes. Many patients also suffer from neurological complications. By using mice carrying a human Kir6.2 mutation (Val(59) to Met(59); nV59M mice) targeted to neurones, we show that these mutations also result in altered anxiety behaviour. The light/dark box, successive alleys and elevated plus maze tasks revealed that nV59M mice have reduced anxiety related responses. Additionally, nV59M mice displayed enhanced basal locomotor activity and exploratory behaviour, as assessed by the low anxiety open-field test. These findings, in combination with previously reported hyperactivity of nV59M mice, appear to correlate with the increased impulsivity and inattentiveness reported in iDEND/DEND patients.

SUBMITTER: Lahmann C

PROVIDER: S-EPMC5576528 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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A mutation causing increased KATP channel activity leads to reduced anxiety in mice.

Lahmann Carolina C Clark Rebecca H RH Iberl Michaela M Ashcroft Frances M FM

Physiology & behavior 20140225

Activating mutations in the Kir6.2 (KCNJ11) subunit of the ATP-sensitive potassium channel cause neonatal diabetes. Many patients also suffer from neurological complications. By using mice carrying a human Kir6.2 mutation (Val(59) to Met(59); nV59M mice) targeted to neurones, we show that these mutations also result in altered anxiety behaviour. The light/dark box, successive alleys and elevated plus maze tasks revealed that nV59M mice have reduced anxiety related responses. Additionally, nV59M ...[more]

PMID: 24582665

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Project description:Neurodevelopment is a tightly coordinated process, in which genome is exposed to spectra of endogenous agents at different stages of differentiation. Increasing body of evidence suggests that DNA damage is an important feature of developing brain, tightly linked to gene expression programs and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, recognized by DNA glycosylases and repaired through base excision repair (BER). The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). Recently we showed that, besides participation in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the evidence of potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout (Aag-/-) mice, we show that Aag absence leads to reduced DNA damage levels, evident in lowered number of γH2AX foci in P5 hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Analysis of gene expression in hippocampus and prefrontal cortex, at multiple developmental stages, indicates that lack of Aag results in altered gene expression, primarily of genes involved in regulation of response to stress. One of the most prominent genes deregulated in Aag-dependent manner, at all tested developmental stages, is aldehyde dehydrogenase 2 (Aldh2). In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag-/- mice exhibit altered behavior, evident in decreased anxiety in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior.

Dataset Information

A mutation causing increased KATP channel activity leads to reduced anxiety in mice.

Publications

A mutation causing increased KATP channel activity leads to reduced anxiety in mice.

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