Genetic Basis Of Cortical Malfunction In Schizophrenia

National Institute Of Mental Health

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Abstract

Cortical dysfunction has been implicated in the pathophysiology of schizophrenia. AKT1-dependent molecular p-ways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. We provide evidence that a functional variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with AKT1 variation. Neuroimaging measures show a main affect of the AKT1 genotype, with significant epistasis with the catechol-O-methyltransferase (COMT) functional polymorphism (val158met), a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role AKT1 in dopaminergic signaling. We also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefronta-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.[unreadable] [unreadable] Increased risk for complex illness genetically is depended upon many genes with subtle effects. The observation that an interaction with COMT adds biologic plausibility for risk genes shows the importance of epistatic effects in mediating the strength of genetic association in psychiatric disorders.[unreadable] We have shown a biologic plausibility of an impact of COMT on the risk profile of several schizophrenia risk genes. GRM3 genotype was associated with inefficient prefrontal engagement and altered prefrontal coupling on the background of COMT val/val. Conversely, COMT Met/Met mediated against the effect of GRM3 genotype. Furthering our study of gene-gene interactions, we investigated the effect of genetic variation of dopamine inactivation via COMT and dopamine transporter (DAT) on hippocampal activity during different memory conditions. We studied the effect of the COMT val158met and the DAT 3 variable number tandem repeat polymorphisms on function of the hippocampus during encoding of recognition memory. Our results demonstrated a double dissociation for the DAT 9-repeat alleles modulated activity in the hippocampus in the exact opposite direction of DAT10/10-repeat alleles based on COMT val158met genotype. Another study examined epistasis between 5-HTTLPR and BDNF, functional polymorphisms of the serotonin (5-HT) transporter gene (SLC6A4). Recent clinical studies suggest that the BDNF met allele has a protective effect regarding the development of depression. Here we show, the BDNF met allele protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate. Our data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotropic signaling on the neural systems level, and have implications for personalized treatment planning in depression. The goal of this research was to identify neural systems mediating the genetic interaction of 5-HTTLPR and BDNF val66met. [unreadable] [unreadable] The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We studied whether a group of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, PRODH, NRG1, RGS4 TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. Many studies have shown that the prevalence of obstetric complications is higher in individuals with schizophrenia which has led to the theory that serious obstetric complications interact with genetic risk factors to increase risk. We sought to empirically test whether serious obstetric complications statistically interact with genes thought to be regulated at least in part by hypoxia in a family-based study. Of the13 schizophrenia susceptibility genes tested, 4 showed significance (AKT1, BDNF, GRM3, and DTNBP1). The hippocampus is especially sensitive to hypoxic injury. AKT1, BDNF, GRM3, and DTNBP1 all play a neuroprotective role. The causal variants in these genes reduce expression levels of the neuroprotective products of these genes, leading to vulnerability to hypoxic insult during neurodevelopment.[unreadable] [unreadable] Looking again at how a genetic variant may impact risk for schizophrenia, we studied at effect of BDNF val66met on measures of N-acetyl-aspartate (NAA) containing compounds using proton magnetic resonance spectroscopic imaging (MRSI) in a population of healthy controls. The BDNF val/met substitution does not affect BDNF protein function, it impacts the regulated secretion of the mature peptide by altering intracellular trafficking and protein packaging. Val/met subjects exhibited significantly reduced levels of left hippocampal NAA/CRE and NAA/CHO compared with val/val subjects. This effect was independent of age, IQ, number of voxels, hippocampal volume, or grey matter content in the voxels of interest. Analysis of other regions showed no effect of BDNF genotype on NAA measures. We confirm previous studies that the association between the BDNF-met variant and reduced levels of hippocampal NAA found in a similar technique. This study adds to the evidence that the BDNF val/met genotype affects hippocampal biology with implications for a variety of neuropsychiatric disorders. BDNF has been implicated in hippocampal plasticity, hippocampal-dependent memory, and is widely distributed in the central nervous system.