Thursday, November 15, 2007

(One of) The gene for PPI discovered

Prepulse inhibition is an enduring phenotype of schizophrenia. In simple words, PPI is the diminished startle response exhibited by an organism, when a weaker stimulus precedes a stronger, normally-startle-response-producing stimulus. It is believed that PPI deficits result from the sensorimotor gating deficits present in Schizophrenia probands. the graphic below shows how the normal prepulse inhibition works. In schizophrenia, this doesn't quite work and the startle response does not diminish with a prepulse being present.

A recent study by Akiko et al in PLOS biology has found a gene that , when knocked out in mice, led to PPI deficits akin to that seen in Schizophrenia. They also used Quantitative Trait Loci method to find the gene associated with PPI and found FABP7 to fit the bill. I present here, the abstract, author's summary and conclusion.

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.

The evidence accumulated in this study consistently supports causation by Fabp7 as the sole gene or one of the multiple genetic substrates underlying the Chromosome-10 QTL of PPI. The gene's effects may be exerted through differential regulation of transcript levels in B6 and C3 mice at a critical period. Importantly, the FABP7 gene, which is modestly associated with schizophrenia in the current study, has the potential to link together the three compelling etiological hypotheses of schizophrenia, namely the NMDA, developmental, and glial (astrocyte) theories . The gene appears to make a larger contribution to PPI and schizophrenia in males. The remaining newly identified but uncharacterized QTLs in this study should provide a valuable resource for continuing molecular studies into PPI and schizophrenia mechanisms. Finally, there are no established prophylactic interventions for schizophrenia. Our results raise the possibility of cohort studies to examine whether replenishment of DHA in pregnant mothers can be beneficial in reducing the chance of schizophrenia development in their offspring, especially for high-risk families. Such analyses should preferably take into account genotypes that affect function and expression of FABP7 via both direct and indirect mechanisms.

I am excited by this research. The endophenotype-leading-to-genotype sort of research is very promising in that it treats complex disorders like schizophrenia one small step at a time and by identifying genes that may be underlying the schizophrenic condition, give us insights into the mechanisms involved. Anyway, I myself strongly believe that sensory gating theory of schizophrenia is on the right track and studies like these can only lead us closer to solving the mystery. One particular thing to note is that FABP7 has differential sex effects with its effects being more prominent in males and this too fits nicely with the fact that schizophrenia is more common in males and occurs at earlier age.

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Buffalo, N.Y. said...

I am fascinated by this PPI theory. I am 40 and my mother died 5 years ago. She was a paranoid schizophrene. She was 78 when she died but she abused all the kids in the family since she had the first of 10 in the 40's. My father never got her help. It was amazing to watch her dillusions unfold. I wish she were still around so I could scare her and see what would happen using PPI. I am wondering if you can remove the gene that causes it somehow in the future. It's such a strange thing to be cursed with. -Buffalo, N.Y.

copperkettle78 said...

Another interesting thing is that FABP7 is induced by reelin signaling pathway, and reelin is itself linked to schizophrenia; moreover, the levels of reelin are low in the postmortem studies of the patients; but curiously the SNPs that are linked to SCHZ show significant correlations only in females.