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 language | English (US) |
---|---|
Pages (from-to) | 4239-4254 |
Number of pages | 16 |
Journal | Human molecular genetics |
Volume | 18 |
Issue number | 22 |
DOIs | |
State | Published - 2009 |
Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by grants to H.O. from Ministry of Education, Culture, Sports, Science and Technology of Japan (16390249, 16650076, 18390254, 18650097, Research on Pathomechanisms of Brain Disorders: 17025017, 18023014, 20023011), the research grant (19A-8) for Nervous and Mental Disorders from Ministry of Health Labor and Welfare, and grants from Uehara Memorial Foundation and The Tokyo Biochemical Research Foundation.