Knock-down of PQBP1 impairs anxiety-related cognition in mouse

Hikaru Ito, Natsue Yoshimura, Masaru Kurosawa, Shunsuke Ishii, Nobuyuki Nukina, Hitoshi Okazawa

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

PQBP1 (polyglutamine tract-binding protein 1) is a causative gene for a relatively frequent X-linked syndromic and non-syndromic mental retardation (MR). To analyze behavioral abnormalities of these patients from molecular basis, we developed a knock-down (KD) mouse model. The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently. After confirming that PQBP1 is selectively suppressed to nearly 50% of the control mice, we performed behavioral analyses of PQBP1-KD mice. The KD mice possessed normal ability in ordinary memory tests including water-maze test, whereas they showed abnormal anxiety-related behavior in light/dark exploration test and open-field test and showed obvious declines of anxiety-related cognition in the repetitive elevated plus maze or novel object recognition test. Correspondingly, we found c-fos upregulation and histone H3 acetylation after behavior tests were declined in neurons of amygdala, prefrontal cortex and hippocampus. Furthermore, we found that 4-phenylbutyric acid, an HDAC inhibitor, efficiently improved expression of these genes and rescued the abnormal phenotypes in adult PQBP1-KD mice. These results suggested that PQBP1 dysfunction in regulating gene expression might underlie the abnormal behavior and cognition of PQBP1-KD mice and that the recovery of expression of such PQBP1 target genes might improve the symptoms in adult patients.

Original languageEnglish (US)
Pages (from-to)4239-4254
Number of pages16
JournalHuman molecular genetics
Volume18
Issue number22
DOIs
StatePublished - Nov 9 2009

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    Ito, H., Yoshimura, N., Kurosawa, M., Ishii, S., Nukina, N., & Okazawa, H. (2009). Knock-down of PQBP1 impairs anxiety-related cognition in mouse. Human molecular genetics, 18(22), 4239-4254. https://doi.org/10.1093/hmg/ddp378