Little more than 35 years ago, the notion that domineering mothers could induce
schizophrenia in their children with their overbearing, identity-extinguishing behavior still held sway among psychiatrists. By the mid-1970s, the schizophrenogenic-mother hypothesis lost favor to genetic explanations of the disease.
Researchers now believe that multiple
genes interact with environmental factors, such as birth trauma or perinatal infection, to cause schizophrenia. And though defects in several chromosomes have been linked to schizophrenia, the hunt for candidate genes continues.
Although the disease''s trademark delusions, hallucinations, social withdrawal, and emotional flattening typically emerge in late adolescence or early adulthood, schizophrenia appears to be a developmental rather than a degenerative disorder. Evidence from human patients suggests that disrupted fatty
acid metabolism may promote susceptibility, and efforts to understand how different drugs control schizophrenia''s symptoms have implicated several brain neurotransmitters, including dopamine, glutamate, and serotonin. Increasing evidence also suggests that defective glial cellswhich not only support other brain cells but also control their activitymay cause the disease.
In a new study, Akiko Watanabe et al. identify a candidate
gene that links abnormal lipid metabolism to glial and developmental theories of schizophrenia. The gene, called Fabp7 (Fatty acid binding protein 7), encodes a protein that helps the essential fatty acid docosahexaenoic acid (DHA) assume its proper shape. It also has functional links to the glutamate receptor N-methyl-D-aspartic acid (NMDA).
In schizophrenia, deficits in the brain''s sensory gating mechanisms, which prevent sensory overload, disrupt a person''s ability to perceive or process information, leading in turn to abnormal thoughts (hearing voices) or actions (frenetic pacing or repetitive hand gestures). One such gating mechanism, called prepulse inhibition (PPI), can be studied by measuring the acoustic startle reflex in mice. In normal mice, PPI suppresses the startle reflex in response to an unexpected
sound that is immediately preceded by a lower-intensity sound. PPI, which is common in schizophrenia, serves as a measurable, internal biological marker for the disease. Researchers hope that identifying the genes responsible for PPI will point to genes that increase risk for schizophrenia.
Toward that end, Watanabe et al. screened four mouse strains for differences in their PPI responses. The researchers selected offspring of the two strains with the highest (the B6 strain) and lowest (C3) responses for experimental testing and genetic analysis. Working with over 1,000 mice, they measured the amplitude and latency (delay between stimulus and maximum response) of the animals'' acoustic startle reflex and their PPI over a range of prepulse sound levels.
To identify the gene variants (or alleles) that contribute to a complex, or quantitative, trait like schizophrenia (or its proxy, PPI), the researchers used quantitative trait loci (QTL) analysis, a statistical method that estimates the likelihood that specific loci (called quantitative loci) affect the trait (or phenotype) under study. The researchers collected genetic data from all 1,010 second-generation
mice using 80 markers called microsatellites, short stretches of repeat DNA sequences with high mutation rates that provide a handy way of assigning individuals to different groups based on their microsatellite genotypes. They sorted mice into 21 groups with about 50 individuals each, and then measured their phenotypes (PPI at the different sound levels, acoustic startle reflex, and latency).
Using a computational model designed to detect QTL signals across the whole genome, the researchers identified six chromosomes with potential contributions to PPI, including a strong candidate on Chromosome 10. Next, they used a different computation
More abstracts about the A Candidate Gene for a Biological Marker of Schizophrenia in Mice