Neuregulin 1 Expression and Electrophysiological Abnormalities in the Neuregulin 1 Transmembrane Domain Heterozygous Mutant Mouse

Abstract

BackgroundThe Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile.MethodsUsing exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine.ResultsIn both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice.InterpretationWe found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…cleaved fragment), although it is not clear how the absence of proteolytic processing may effect Nrg1 neurobiological activity. The current findings suggest that Nrg1 expression may dynamically influence expression of NMDARs as a function of age, brain region and cohort differences, consistent with the varying patterns of Nrg1 expression across the lifespan (Long et al 2015).…”

“…Gamma oscillations occur between 25-100Hz and reflect the synchronous activity of distinct neuronal populations producing brain states that are thought to contribute to conscious awareness and attention, and some authors have likened the elevation in baseline gamma oscillations in diseases such as schizophrenia to neural "noise" brought about by dysfunction of the GABAergic system (Gandal et al 2012). Putative neural "noise" in the form of baseline gamma oscillations is increased in the parietal cortex in TM Nrg1 mice (Long et al 2015), and also in the prefrontal cortex in ErbB4 hypomorphic mice (Hou et al 2014) when compared with control mice. Similarly, baseline synaptic firing of somatosensory neurons in EGF-like domain "knockout" mice is significantly above control levels.…”

“…reduced gene expression) mice. Subsequently, several studies have attempted to replicate this finding, but confirmatory evidence has been limited (Bjarnadottir et al 2007;Long et al 2015;Newell et al 2013). Some studies have indicated that the effects of reduced Nrg1 on NMDAR expression vary dependent on age and brain region analysed.…”

“…Two further studies employing the TM Nrg1 model found reduced NMDAR subunit phosphorylation in both hippocampus (Bjarnadottir et al 2007) and prelimbic (i.e. prefrontal) cortex (Long et al 2015). Hence, there has been considerable inconsistency between findings, which render the effects of the TM Nrg1 model on the NMDAR quite ambiguous.…”

“…Nevertheless, recent work suggests that these TM Nrg1 mice may not be a simple loss-of-function model, as exons upstream of the genetic deletions appear to have normal levels of expression (Long et al 2015) and theoretically this model may still generate functionally mature Nrg1 (i.e. cleaved fragment), although it is not clear how the absence of proteolytic processing may effect Nrg1 neurobiological activity.…”