ErbB4 Genotype Predicts Left Frontotemporal Structural Connectivity in Human Brain

Abstract

Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)-ErbB4 receptor complex are associated with schizophrenia illness. As NRG1--ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)Fa putative measure of neuronal myelinationFis predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N ¼ 59; mean age: 22.6 ± 1.8 years). We also measured reaction time (RT) during a selective attention/ working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FAgenotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA.

Correlation of Brain White Matter Diffusion Anisotropy and Mean Diffusivity with Reaction Time in an Oddball Task

“…Fifty-one healthy subjects (mean age: 22.6 8 1.7 years, 26 males) were investigated as described previously for an overlapping sample [12] . Subjects were recruited via local newspaper announcements.…”

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

“…NRG1-ErbB4 signaling plays a critical role in neural development and synaptic plasticity (10-12) and NRG1 and ErbB4 mutant mice exhibit behavioral alterations (2, 12-14) consistent with other murine models of schizophrenia (15). Schizophrenia-associated genetic variation in these genes is implicated in human brain structure and function (6,16,17), but the biological mechanisms accounting for these diverse effects and how they translate into illness are unclear.Increased NRG1 and ErbB4 expression has been observed in schizophrenia postmortem brain tissue (5, 7, 18) and in neurons derived from induced pluripotent stem cells (IPSCs) of patients (19). Risk-associated polymorphisms in these genes affect expression of specific NRG1 and ErbB4 isoforms in human brain (7,18,20).…”

“…NRG1-ErbB4 signaling plays a critical role in neural development and synaptic plasticity (10-12) and NRG1 and ErbB4 mutant mice exhibit behavioral alterations (2, 12-14) consistent with other murine models of schizophrenia (15). Schizophrenia-associated genetic variation in these genes is implicated in human brain structure and function (6,16,17), but the biological mechanisms accounting for these diverse effects and how they translate into illness are unclear.…”

Diffuse Abnormality of Low to Moderately Organized White Matter in Schizophrenia

“…Of particular importance, FA appears to be heritable in SCZ, with high correlations in monozygoticaffected twins and heritability in unaffected relatives (Camchong et al, 2009). SNPs in ERBB4 (Konrad et al, 2009), NEUREGULIN1 (McIntosh et al, 2008Winterer et al, 2008), and DISC1 (Hashimoto et al, 2006) have been associated with decreased FA in healthy controls. It is possible that a focus on FA values of 0.25 to 0.5 will improve the sensitivity and reproducibility of these types of analyses.…”