Expression of the Neuregulin Receptor ErbB4 in the Brain of the Rhesus Monkey (Macaca mulatta)

Jörg Neddens,Andrés Buonanno,Manuel S Malmierca

doi:10.1371/journal.pone.0027337

Abstract

We demonstrated recently that frontal cortical expression of the Neuregulin (NRG) receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons. Here, using highly-specific monoclonal antibodies, we provide the first extensive report of ErbB4 protein expression throughout the cerebrum of primates. We show that ErbB4 immunoreactivity is high in association cortices, intermediate in sensory cortices, and relatively low in motor cortices. The overall immunoreactivity in the hippocampal formation is intermediate, but is high in a subset of interneurons. We detected the highest overall immunoreactivity in distinct locations of the ventral hypothalamus, medial habenula, intercalated nuclei of the amygdala and structures of the ventral forebrain, such as the islands of Calleja, olfactory tubercle and ventral pallidum, and medium expression in the reticular thalamic nucleus. While this pattern is generally consistent with ErbB4 mRNA expression data, further investigations are needed to identify the exact cellular and subcellular sources of mRNA and protein expression in these areas. In contrast to in situ hybridization in rodents, we detected only low levels of ErbB4-immunoreactivity in mesencephalic dopaminergic nuclei but a diffuse pattern of immunofluorescence that was medium in the dorsal striatum and high in the ventral forebrain, suggesting that most ErbB4 protein in dopaminergic neurons could be transported to axons. We conclude that the NRG-ErbB4 signaling pathway can potentially influence many functional systems throughout the brain of primates, and suggest that major sites of action are areas of the “corticolimbic” network. This interpretation is functionally consistent with the genetic association of NRG1 and ERBB4 with schizophrenia.

Highlights

Single nucleotide polymorphisms (SNPs) in the genes encoding Neuregulin-1 (NRG1) and its receptor ErbB4 are associated with increased risk for and endophenotypes of schizophrenia [1,2,3]; NRG1 is associated with bipolar disorder [4,5]
Images presented at original resolution show that cortical immunolabeling occurred in small somata that were scattered throughout the cortex, and in the surrounding neuropil (Figure 1B), consistent with our recent description of selective ErbB4 expression in a subset of interneurons in the prefrontal cortex of rhesus monkeys [12]
We present our findings arranged in functional systems, and we start with areas of the ‘‘corticolimbic system’’ [43,44,45] that are important for the proper execution of different types of memory, attention and goal-directed behavior, and emotion and reward

Summary

Introduction

Single nucleotide polymorphisms (SNPs) in the genes encoding Neuregulin-1 (NRG1) and its receptor ErbB4 are associated with increased risk for and endophenotypes of schizophrenia [1,2,3]; NRG1 is associated with bipolar disorder [4,5]. Studies in the frontal cortex and hippocampus of rodents have shown that acute activation of ErbB4 by bath application of NRG1 modulates GABAergic transmission [13,14,15] and synaptic plasticity at glutamatergic synapses [16,17,18,19]. NRG1-ErbB4 signaling acutely augments hippocampal gamma oscillations [21] and promotes the generation and migration of cortical interneurons [22,23] as well as the formation and maintenance of interneuron synapses [15,24]. The finding of recruitment of GABAergic, glutamatergic and dopaminergic signaling by the NRG1-ErbB4 pathway provides a biologically plausible mechanism that is consistent with its genetic association (see above) and consolidates many hypotheses on the involvement of different neurotransmitter systems in the etiology of schizophrenia (reviewed in [3])

Methods

Results

Conclusion