Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype.
Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming.
Watanabe
Akiko
A
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
Toyota
Tomoko
T
Owada
Yuji
Y
Hayashi
Takeshi
T
Iwayama
Yoshimi
Y
Matsumata
Miho
M
Ishitsuka
Yuichi
Y
Nakaya
Akihiro
A
Maekawa
Motoko
M
Ohnishi
Tetsuo
T
Arai
Ryoichi
R
Sakurai
Katsuyasu
K
Yamada
Kazuo
K
Kondo
Hisatake
H
Hashimoto
Kenji
K
Osumi
Noriko
N
Yoshikawa
Takeo
T
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D007266:Inhibition, Psychological; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors
C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate