TNF receptors 1 and 2 exert distinct region‐specific effects on striatal and hippocampal grey matter volumes (VBM) in healthy adults

Abstract

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.

Polymorphic Variants of TNFR2 Gene in Schizophrenia and Its Interaction with -308G/A TNF-α Gene Polymorphism

“…It was revealed that the changes in both microstructure and function of the brain between men and women were associated with the varied presentation of aggression, impulsivity, and excitement in schizophrenia [ 22 – 24 ]. It was shown that genetic variants of TNFR1 and TNFR2 are associated with the striatal and hippocampus morphology in healthy people [ 18 ]. It is worth noting that there have been revealed participation of tested SNPs of TNFR2 gene in the modulation of symptoms of the central nervous system which coexist with other diseases.…”

“…An increase in the frequency of some alleles in the human TNFR2 gene has been correlated with decreased TNFR2 expression [ 17 ]. The rs1061624 SNP was also associated with a hippocampus volume in healthy adults [ 18 ]. The rs1061622 (T/G) SNP is located in exon 6 at 676 nucleotide of TNFR2 gene.…”

Microglial regional heterogeneity and its role in the brain

“…So far, studies revealing the heterogenous functions of microglia and microglial molecules in different human brain regions have been rare. In an imaging genetics study, respective roles of TNFα receptors, i.e., TNFR1 and TNFR2, in regulation of hippocampal and striatal morphologies in healthy human subjects was explored [87]. TNFα is one of the key microglia-derived cytokines that are known to regulate synaptic transmission and cognition [88].…”

“…TNFR1 and TNFR2 are microglial receptors exerting opposite effects on neuronal survival, with TNFR1 being neurodegenerative and TNFR2 neuroprotective [89]. Interestingly, TNFRSF1A (encoding TNFR1) single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 were found to have highly significant genotypic associations with striatal but not hippocampal volume, whereas TNFRSF1B (encoding TNFR2) SNP rs1061624 yielded a significant association with hippocampal but not striatal volume [87]. In addition, a most recent transcriptomic study evaluating celltype-specific contribution to cortical thickness in the adolescent human brain showed that inter-regional profiles in cortical thickness were 70% dependent on those in the expression of genes marking CA1 pyramidal cells, astrocytes, and microglia; and these genes were also related to age-dependent cortical thinning [90].…”

The Limbic System in Youth Depression: Brain Structural and Functional Alterations in Adolescent In-patients with Severe Depression

“…T1-weighted high resolution anatomical images were acquired (Gyroscan Intera 3T, Philips Medical Systems, Best, NL) with a 3D fast gradient echo sequence ('Turbo Field Echo', TFE), TR= 7.4 ms, TE = 3.4 ms, FA = 9°, two signal averages, inversion prepulse every 814.5 ms, acquired over a field of view of 256(FH) × 204 (AP) × 160(RL) mm, phase encoding in AP and RL direction, reconstructed to cubic voxels of 0.5 × 0.5 × 0.5 mm. The VBM8toolbox (http://dbm.neuro.uni-jena.de/vbm) was used for preprocessing the structural images with default parameters as described before Redlich et al, 2016;Stacey et al, 2016). Briefly, images were bias-corrected, tissue classified, and normalized to MNI-space using linear (12-parameter affine) and nonlinear transformations, within a unified model including high-dimensional DARTEL-normalization and smoothed with a Gaussian kernel of 8 mm full width half maximum (FWHM).…”