Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

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Abstract
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. A startle response to an unexpected, strong startling stimulus can be suppressed by an immediately preceding low-intensity stimulus, thereby eliciting little behavioral response. This phenomenon, called prepulse inhibition (PPI), has been observed in all mammals tested and is thought to reflect sensory-motor gating functions in organisms. PPI is diminished in human schizophrenia, raising the possibility that PPI might serve as a potential biological marker for the disease. Once the genes regulating PPI in lower animals are identified, it is expected that the human orthologs will be strong candidate genes for schizophrenia. In this study, we first performed a genetic dissection of mouse PPI using quantitative trait loci analysis, which detects chromosomal regions harboring causative genes. Further analyses including those of knockout mice, allowed us to identify one potential causative gene, Fabp7 (fatty acid binding protein 7, brain), a chaperon for the essential fatty acid docosahexaenoic acid. Human studies showed that the FABP7 gene is modestly associated with schizophrenia and that transcript expression levels are up-regulated in schizophrenic brains. From these results, we propose that a FABP7 protein-mediated disturbance of essential lipid metabolism in developing brains may be one risk factor in the development of schizophrenia, with a greater effect in males.