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. 2020 Apr 21:14:351.
doi: 10.3389/fnins.2020.00351. eCollection 2020.

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

Suping Cai  1 , Yahui Lv  1 , Kexin Huang  1 , Wei Zhang  1 , Qiang Wang  2 , Liyu Huang  1 , Jijun Wang  3
Affiliations

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

Suping Cai et al. Front Neurosci. .

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-striatum-thalamus 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.

Keywords: causality connection; glutamic pathway; magnetic resonance imaging; schizophrenia; single nucleotide polymorphism.

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Figures

FIGURE 1
FIGURE 1
Diagram explaining the selection of the frontal-striatum-thalamus pathway. (A) Detailed cortex-striato-pallido-thalamus pathway at the molecular level, this figure is from Carlsson et al. (1999); (B) several key glutamic pathways in synaptic release level, this figure from Schwartz et al. (2012); (C) selected frontal-striatum-thalamus pathway. Abbreviations: Glu, Glutamate; DA, dopamine; GABA, gamma aminobutyric acid.
FIGURE 2
FIGURE 2
Rs11146020 and rs3813296 main effects on causality connections and relationships with behavioral variables (P < 0.01, FDR correction). (A) rs11146020 and (B) rs3813296 main effects on causality connections; (C) causality connection strength of L. dLPFC → R. dLPFC has significant positive correlation with duration of untreated psychosis in patients with the GG genotype; (D) causality connection strength of R. dLPFC → R. caudate has a significant positive correlation with BVMT scores in patients with the TT genotype; causality connection strength of R. dLPFC → R. thalamus has a significant positive correlation with BVMT-R scores (E) and verbal fluency test scores (F) in patients with the TT genotype. Abbreviations: dLPFC, dorsolateral prefrontal cortex; BVMT-R, brief visuospatial memory test, revised.
FIGURE 3
FIGURE 3
Interaction effect of rs11146020 and rs3813296 on causality connections and relationship with behavioral variables (P < 0.01, FDR correction). (A) interaction effect of rs11146020 and rs3813296 on causality connections; causality connection strength of R. pallidum → R. dLPFC (B), L. pallidum → L. dLPFC (D) and L. pallidum → R. dLPFC (E) has a significant negative correlation with MSCEIT-ME in patients with the GG/GT genotype; causality connection strength of R. pallidum → R. caudate (C) has a significant negative correlation with MSCEIT-ME in patients with the CG/TT genotype; Abbreviations: dLPFC, dorsolateral prefrontal cortex; MSCEIT-ME, Mayer-Salovey-Caruso emotional intelligence test (managing emotions).
FIGURE 4
FIGURE 4
Main and interaction effects of rs11146020 and rs3813296 on gray and white matter (P < 0.01, FDR correction). (A) rs11146020 and rs3813296 interaction effect on gray matter volume (GG/GT vs. GG/TT); (B) rs3813296 main effect on white matter volume (GT vs. TT); (C) rs11146020 and rs3813296 interaction effect on white matter volume (GG/GT vs. CG/TT).
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