Knock-down of PQBP1 impairs anxiety-related cognition in mouse.
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.
Ito
Hikaru
H
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, Japan.
Yoshimura
Natsue
N
Kurosawa
Masaru
M
Ishii
Shunsuke
S
Nukina
Nobuyuki
N
Okazawa
Hitoshi
H
D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism / Q000523:psychology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003071:Cognition; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C492272:Pqbp1 protein, mouse