Human Molecular Genetics Advance Access originally published online on August 6, 2009
Human Molecular Genetics 2009 18(22):4239-4254; doi:10.1093/hmg/ddp378
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Knock-down of PQBP1 impairs anxiety-related cognition in mouse
1 Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, 2 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan and 3 Laboratory for Molecular Genetics, RIKEN Tsukuba Institute, Ibaraki 305-0074, Japan
* To whom correspondence should be addressed. Email: okazawa-tky{at}umin.ac.jp
Received May 7, 2009; Accepted August 4, 2009
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.