Regulation of neuregulin expression in the injured rat brain and cultured astrocytes

Abstract

In this report, we investigated whether reactive astrocytes produce neuregulins (glial growth factor 2/heregulin/acetylcholine receptor-inducing activity or neu differentiation factor) and its putative receptors, ErbB2 and ErbB3 tyrosine kinases, in the injured CNS in vivo. Significant immunoreactivities with antineuregulin, anti-ErbB2, and anti-ErbB3 antibodies were detected on astrocytes at the injured site 4 d after injury to the adult rat cerebral cortex. To elucidate the mechanisms for the upregulation of neuregulin expression in astrocytes, primary cultured astrocytes were treated with certain reagents, including forskolin, that are known to elevate the intracellular level of cAMP and induce marked morphological changes in astrocytes. Western blot analysis showed that the expression of a 52 kDa membrane-spanning form of a neuregulin protein was enhanced in cultured astrocytes after administration of forskolin. The upregulation of glial fibrillary acidic protein was also observed in astrocytes treated with forskolin. In contrast, inactivation of protein kinase C because of chronic treatment with phorbol ester 12-O-tetradecanoyl phorbol 13-acetate downregulated the expression of the 52 kDa isoform, although other splice variants with apparent molecular sizes of 65 and 60 kDa were upregulated. These results suggest that the enhancement of neuregulin expression at injured sites is induced, at least in part, by elevation in intracellular cAMP levels and/or a protein kinase C signaling pathway. The neuregulin expressed on reactive astrocytes may stimulate their proliferation and support the survival of neurons surrounding cortical brain wounds in vivo.

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

“…1,5 NRG1 expression is induced by adult ischemic and traumatic brain injury, as well as by neonatal hypoxia. [9][10][11] Thus, it is possible that the more abnormal expression of NRG1 is induced in human embryos or neonates carrying these SNPs by these environmental insults, the more severely this factor might impair brain development to increase the risk of schizophrenia.…”

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

“…Brain injury induces NRG-1 protein expression in astrocytes of rat cerebral cortex. 30 Curare blockade of nicotinic receptors reduces the expression of type 1 protein in chick motor neurons, an effect that can be prevented by brain-derived neurotrophic factor and neurotrophin 3. 31 In the central nervous system, NRG-1 promotes the switch from the immature form of NMDAR, which contains primarily NR2B subunits to one containing more NR2C subunits.…”

Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord

“…47,48 Interestingly, these neuregulins are highly expressed by reactive astrocytes at the lesion site in the injured CNS. 49 In the intact spinal cord, only minimal proliferation of OEG is expected because of very little astrocytic scarring and contact inhibition. Based on the increase in p75 NTR immunoreactivity over time, proliferation of implanted OEG in the lesioned spinal cord seems to occur although the additional staining for p75 NTR could also be due to Schwann cells that have been reported previously to invade spinal cord lesion sites.…”