Genetic Association of ErbB4 and Human Cortical GABA LevelsIn Vivo

Abstract

NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4 dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy (MRS) in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p=0.014), but not GLX (p=0.51), with A allele carriers having higher GABA as predicted by their impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders.

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

“…How does antipsychotic treatment affect GABA levels? Based on our preliminary data, previous studies in medicated patients (18,20), our genetic data in controls (22,23)-all acquired in the dorsal anterior cingulate-and results of untreated patients in the medial prefrontal cortex (19), we hypothesized that GABA levels would be increased in treated and untreated patients with schizophrenia as compared with healthy controls and that if this were a reflection of increased genetic risk, then levels in unaffected siblings would fall somewhere in between. We also hypothesized that antipsychotic treatment would decrease GABA levels, and we tested this hypothesis by studying the relationship between antipsychotic dosage and GABA levels in treated patients, and additionally comparing GABA levels on and off medications in a subset of patients scanned in both conditions.…”

“…Marenco et al (22,23) showed that single-nucleotide polymorphisms in GAD1 and ErbB4 linked with increased risk for schizophrenia were associated with elevated GABA levels in the dorsal anterior cingulate, but these results were observed in healthy subjects. These data may support the reported increase in GABA levels in the prefrontal cortex of patients with schizophrenia (19,20) and imply that this increase may have genetic underpinnings.…”

Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans

“…The physiological effects of both polymorphisms have already been documented (Luykx et al, 2012;Marenco et al, 2011;Zhao et al, 2006).…”

“…The T allele has been shown to be associated with increased GABA concentration in human cerebrospinal fluid (Luykx et al, 2012) and in the dorsal anterior cingulate gyrus (Marenco et al, 2011). The ErbB4 gene is of particular interest, as it codes for one of the ErbB receptor tyrosine kinases activated by neuregulin 1 (NRG1).…”

Finding a druggable target for schizophrenia

“…Genetics studies over the past few years have found a strong association between polymorphisms, common genetic variation, and structural deletions in the gene encoding for neuregulin-1 (NRG1) and its receptor ERBB4 with risk for schizophrenia (4)(5)(6)(7)(8). In particular, risk polymorphisms in ERBB4 that predict increased expression of the ERBB4 cytoplasmic isoform-1 (CYT-1) receptor isoform and GABA levels in human cortex have attracted a lot of attention (7,9,10). The CYT-1 isoform of ERBB4 contains a phosphatidylinositol 3-Kinase (PI3K)-binding site and triggers activation of the PI3K pathway (Fig.…”