Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

Abstract

Genetic variants in GPR85 (SREB2: rs56080411 and rs56039557) have been associated with risk for schizophrenia. Here, we test the hypothesis that these variants impact on brain function in normal subjects, measured with functional magnetic resonance imaging (fMRI) paradigms that target regions with greatest SREB2 expression (hippocampal formation and amygdaloid complex). During a facial emotion recognition paradigm, a significant interaction of rs56080411 genotype by sex was found in the left amygdaloid complex (male risk allele carriers showed less activation than male homozygotes for the non-risk allele, while females showed the opposite pattern). During aversive encoding of an emotional memory paradigm, we found that risk allele carriers for rs56080411 had greater activation in the right inferior frontal gyrus. Trends in the same direction were present for rs56039557 in the right occipital cortex and right fusiform gyrus. During a working memory paradigm, a significant sex-by-genotype interaction was found with male risk allele carriers of rs56080411 having inefficient activation within the left dorsolateral prefrontal cortex (DLPFC), compared with same sex non-risk carriers, while females revealed an opposite pattern, despite similar levels of performance. These data suggest that risk-associated variants in SREB2 are associated with phenotypes similar to those found in patients with schizophrenia in the DLPFC and the amygdala of males, while the pattern is opposite in females. The findings in females and during the emotional memory paradigm are consistent with modulation by SREB2 of brain circuitries implicated in mood regulation and may be relevant to neuropsychiatric conditions other than schizophrenia.

Integrative Brain Transcriptome Analysis Reveals Region-Specific and Broad Molecular Changes in Shank3-Overexpressing Mice

“…Meanwhile, in our GPR85 overexpression experiment, we could observe decreased synapse number because we overexpressed GPR85 very high level for a long period (2 weeks). Considering the associations of GPR85 / SREB2 with ASDs and SCZ ( Matsumoto et al, 2008 ; Chen et al, 2012 ; Radulescu et al, 2013 ; Fujita-Jimbo et al, 2015 ), more investigations about the functional relationship between Shank3 and GPR85 would provide information on the detailed mechanisms of activity-dependent synaptic regulation and their potential implications in multiple brain disorders.…”

Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

“…Although we did not characterize them in details, there were several interesting differentially expressed genes (DEGs) from the striatal RNA-seq analysis of Shank3 TG mice. For example, an up-regulated GPR85 (also called SREB2 for super-conserved receptor expressed in brain) gene, encoding a highly conserved G protein-coupled receptor, has been associated with SCZ (Matsumoto et al, 2008 ; Radulescu et al, 2013 ). Notably, the Gpr85 TG mice mildly overexpressing GPR85 proteins display some abnormal behaviors including impaired prepulse inhibition and decreased social interaction (Matsumoto et al, 2008 ), which were also seen in the Shank3 TG mice (Han et al, 2013b ).…”

Recurrent microdeletion 2q21.1: Report on a new patient with neurological disorders

“…Mutations in GPR56 are responsible for polymicrogyria (MIM 606854) [BahiBuisson and Guerrini, 2013] while GPR98 is associated with familial febrile seizures (MIM 604352) and Usher syndrome type 2C (MIM 605472). In addition, genetic variants in GPR85 have been associated with risk for schizophrenia [Matsumoto et al, 2008;Radulescu et al, 2013]. However, the function of this gene is still unclear.…”