Subsequently, the investigators used MRI spectroscopy to measure the effect of SNP 4 on NAA, an indirect measure of prefrontal glutamate neurotransmission, synaptic abundance, and prefrontal extracellular glutamate. NAA has been previously shown to be lower in DLPFC and hippocampus in

schizophrenia.53 In this study right and left, DLPFC NAA was lower in risk allele homozygotes than other genotypes, as would be expected from the cognitive and fMRI results. Group-by-genotype Inhibitors,research,lifescience,medical MS-275 solubility dmso interaction was not significant; even so, there was scant effect of genotype on NAA in the sibling group. Finally, in postmortem human prefrontal cortex, risk allele homozygotes had significantly lower mRNA levels of the glial glutamate transporter EAAT2.The authors suggest these convergent data reflect a specific molecular pathway Inhibitors,research,lifescience,medical by which GRM3 genotype may alter glutamate neurotransmission, and thus prefrontal and hippocampal physiology and cognition, thereby increasing risk for schizophrenia. Nevertheless, the authors cautiously point out the weakness of GRM3 Inhibitors,research,lifescience,medical effects on intermediate phenotypes in this study, particularly due to the multiple statistical testing, which is unavoidable

in a study of such complexity. This study is paradigmatic of the opportunities and the impediments encountered in a combined multimodal effort to identify genes underlying the neurobiology Inhibitors,research,lifescience,medical of cognitive functions in schizophrenia. Conclusions In many respects, it is eminently reasonable to search for intermediate phenotypes

in complex disorders such as schizophrenia, particularly because the matrix of risk alleles shaping the clinical phenotype will likely turn out to be far more complex than might have been expected. Nevertheless, emerging evidence suggests that, in order to more finely parse the genetic infrastructure, it will be necessary to more finely parse and validate the most relevant functional phenotypes. This conjunction of aims may not be easy to achieve. For example, despite a substantial literature on eye-tracking Inhibitors,research,lifescience,medical dysfunctions in schizophrenia and unaffected siblings,1,114,115 and increasingly precise understanding of the physiology of eye movement, it would seem at first glance difficult to imagine how therapeutic PAK6 normalization would improve the psychosocial outcome for patients with schizophrenia. In essence, that is precisely the reason to identify intermediate phenotypes and the genes modulating their functions; we do not have sufficient evidence to predict which intermediate phenotypes we should ignore. For this reason, it will be important to develop an operational definition of relevance that assigns primacy to putative phenotypes most likely to impact clinical outcome. The apparently incongruent sensory ERP (P50 and P300) data appears in part to be due to the inherent sensitivity of ERP experiments to methodological diferences.