Abstract
Transgenic mice overexpressing the type I isoform of neuregulin 1 (Nrg1; NRG1) have alterations in hippocampal gamma oscillations and an age-emergent deficit in hippocampus-dependent spatial working memory. Here, we examined the molecular and morphological correlates of these findings. Microarrays showed over 100 hippocampal transcripts differentially expressed in Nrg1tg-type I mice, with enrichment of genes related to neuromodulation and, in older mice, of genes involved in inflammation and immunity. Nrg1tg-type I mice had an enlarged hippocampus with a widened dentate gyrus. The results show that Nrg1 type I impacts on hippocampal gene expression and structure in a multifaceted and partly age-related way, complementing the evidence implicating Nrg1 signaling in aspects of hippocampal function. The findings are also relevant to the possible role of NRG1 signaling in the pathophysiology of schizophrenia or other disorders affecting this brain region.
Highlights
Neuregulin 1 (Nrg[1]; NRG1) is a growth factor, signaling via Erbb[3] and Erbb[4] receptor tyrosine kinases
Adopting a stringent statistical approach, and with a 1.5-fold change threshold, we identified over 100 differentially expressed genes, of which ~ 80% were increased in Nrg1tg-type I mice compared with wt (Fig. 1a, and Supplementary Tables 1–3)
Genes upregulated at both ages in the NRG1tg-type I mice included neuropeptide Y (Npy), brain-derived neurotrophic factor (Bdnf), and glial fibrillary acidic protein (Gfap)
Summary
Neuregulin 1 (Nrg[1]; NRG1) is a growth factor, signaling via Erbb[3] and Erbb[4] receptor tyrosine kinases. The type I isoform is affected in schizophrenia, with increased expression in hippocampus[7] and prefrontal cortex[14] compared with controls, and representing one of the abnormalities of NRG1-ErbB4 signaling observed in the disorder[15,16,17,18]. Nrg1tg-type I mice exhibit a reduced frequency of carbachol-induced hippocampal gamma oscillations[22]. These findings complement a broad body of evidence linking Nrg[1] to hippocampal function and plasticity[23,24,25,26,27,28]. Differing phenotypic profiles are seen in other genetic mouse models of Nrg[1], highlighting the existence of isoform-specific properties[29,30,31,32,33,34]
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