Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

Abstract

Objectives: The frontal-striatum-thalamus pathway is important in the glutamic neural circuit. The hypofunction of GRIN1 and GRIA2 subunits from glutamic receptors has been hypothesized as the primary process in the etiology of schizophrenia. Identified gene polymorphism involved in the pathogenesis of schizophrenia may uncover relevant mechanism pathways. Methods: We selected two loci of rs11146020 and rs3813296 distributed in GRIN1 and GRIA2 genes and tested their main and interaction effects on causality connections and structural characteristics in the frontal-striatum-thalamus pathway in 55 Han Chinese first-episode negative schizophrenia patients.Results: We found that: (1) rs11146020 has a significant main effect on the causality connections between the bilateral dorsolateral prefrontal cortex, and rs3813296 mainly influences those of the descending pathway from the prefrontal cortex to the striatum;(2) interaction effect of rs11146020 and rs3813296 on causality connections are located in the ascending pathway from the pallidum to the dorsolateral prefrontal cortex; and (3) the two loci have effects on the volumes of several regions of this pathway. Conclusion:Our results suggested there is modulation on glutamic frontal-striatumthalamus pathway by rs11146020 and rs3813296 gene polymorphism. Patients with different genotypes have different neuroimaging characteristics, which indirectly reminded clinicians those patients should receive different clinical interventions.

Magnetic Resonance Imaging throughout the Clinical Course of Schizophrenia: Neurobiological Underpinnings and Clinical Implications

“…The results show that structural and functional connectivity of the limbic system has changed, including hippocampus, amygdala, etc. [34], as well as insula [35] and thalamus [36], and may consist of part of the mechanism. Changes in these regions based on MRI multi-parameter models are proposed to predict its efficacy [37].…”

Shaping the Trans-Scale Properties of Schizophrenia via Cerebral Alterations on Magnetic Resonance Imaging and Single-Nucleotide Polymorphisms of Coding and Non-Coding Regions

“…Similar to the effect of KIAA0319 SNPs (rs2038136,rs2038137) genotype, the influence of SNP rs4504469 located at the exon of KIAA0319 coding region on the left Broca upper/lower parietal network and bilateral Wernicke-frontalparietal network is reflected only in controls (Jamadar et al, 2013 ). In addition to investigating the influences of SNP rs11146020, which is located in the non-coding region of GRIN1 , Cai et al ( 2020b ) found that SNP rs3813296 located in the intron region of GRIA2 also has certain effects on the causality connections which located on the descending pathway from DLPFC to the striatum and thalamus in patients with schizophrenia. In the meantime, the interaction effects of rs11146020 and rs3813296 on causality connectivity are mainly located in the upstream pathway from the bilateral pallidum to the right caudate and the bilateral DLPFC, and negatively correlated with the Mayer–Salovey–Caruso emotional intelligence test, managing emotions score.…”

“…Compared with non-risk A allele carriers, patients with schizophrenia with G/G genotype of risk variant rs7914558 which is located in intron1 of the CNNM2 have smaller gray matter volumes in the bilateral inferior frontal gyri, especially the orbital region (Ohi et al, 2013 ). Among the effects of GRIA2 gene rs3813296 on white matter (Cai et al, 2020b ), the most significant effect is located on the bilateral superior corona radiata fibers. Compared with the TT genotype, patients with GT genotype have a significantly larger volume of the superior corona radiata, which leads to the dispersion of the connection strength between the left DLPFC and the right caudate (Cai et al, 2020b ).…”

“…Among the effects of GRIA2 gene rs3813296 on white matter (Cai et al, 2020b ), the most significant effect is located on the bilateral superior corona radiata fibers. Compared with the TT genotype, patients with GT genotype have a significantly larger volume of the superior corona radiata, which leads to the dispersion of the connection strength between the left DLPFC and the right caudate (Cai et al, 2020b ). This is seemingly the factor that patients with GT genotype have a decrease in connection strength between the two areas.…”

“…Compared with C allele carriers, NRGN gene rs12807809 TT homozygotes in patients with schizophrenia have significantly lower hippocampus-seeded FC values in bilateral middle cingulate gyri and left anterior cingulate gyrus, suggesting that rs12807809 may be involved in the pathophysiological process of abnormal Papez circuit function (Zhang et al, 2019). The effects of GRIN1 rs11146020 are mainly reflected on the causality connections between the bilateral dorsolateral prefrontal cortex (DLPFC) (Cai et al, 2020b). However, some SNP genotypes are not associated with changes of FC in patients with schizophrenia, demonstrating the uncertainty of genetic factors at the molecular and cellular levels.…”