Prof. Takeo Yoshikawa

Prof. Yoshikawa

ISP2012 Lecture Course Abstract:

Genetic approaches of schizophrenia research from human and animal models

Schizophrenia is one of the two major, adult-onset mental illnesses and the outcome is debilitating. Its prevalence is about 1%, irrespective of geographical area and era, and therefore it is not a rare disease. However, the precise etiology of the disease has remained elusive. Recently, “GABA hypothesis of schizophrenia” has been proposed, mainly from the findings that the expression levels of multiple GABA-related genes are down-regulated in the postmortem brains from schizophrenia, compared to those from controls. We performed a Genome-Wide Association Study (GWAS) of schizophrenia in the Japanese population. By scrutinizing the data, we noticed the accumulation of association signals from GABA-related genes. Therefore, we decided to perform a replication study: we selected 384 tag SNPs (single nucleotide polymorphism) from 25 GABA-related genes and genotyped them using 1,500 patients with schizophrenia and 1,500 controls. Among the 25 genes, 11 genes were replicated. These results suggest that GABAergic system may underlie the genetic architecture of schizophrenia in the Japanese as one of primary causes. In the next step, we examined whether schizophrenia-like behavioral phenotypes can be seen in model mice. The mice were doubly hetero-knocked out of the genes encoding Gad67 and Gad65 (wHT KO), both encoding GABA-synthesizing enzymes. The mice showed dampened prepusle inhibition (see next paragraph), increased aggression in a social interaction test and enhance sensitivity to a hallucinogenic drug, methamphetamine. These results imply that also in mice a deteriorated GABAergic function may lead to human schizophrenia-like phenotypes. The transcript expression analyses using GeneChips detected the altered expression levels of genes that were identified by the aforementioned GWAS. Collectively, our results point to the view that genomic polymorphisms of GABA-related genes are located around one of the central genetic causes of schizophrenia in the Japanese population, by interacting directly/indirectly with other susceptibility genes.
  As an alternative approach, the search for genetic basis for “endophenotype” is also promising. Deficits in prepulse inhibition (PPI) are a biological marker for mental disorders including schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis, on 1010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected 6 major loci for PPI. A promising candidate on the chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene predominantly expressed in neural stem/progenitor cells in developmental stage. Fabp7-deficient mice indeed showed decreased PPI. A quantitative complementation test proved Fabp7 as a PPI-QTL gene. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed genetic association with schizophrenia.
  Finally, I would like to discuss a potential link between GABAergic system and aberrant lipid metabolism in terms of schizophrenia pathology.

Prof. Yoshikawa's ISP2012 Profile
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ISP2012 Abstracts