Neuregulin Induces GABA_AReceptor Subunit Expression and Neurite Outgrowth in Cerebellar Granule Cells

Abstract

Neuregulin (NRG), a growth and differentiation factor that signals via erbB receptor tyrosine kinases, has been shown to have biological effects in both the CNS and the peripheral nervous system. We report here that erbB4 is expressed in mature cerebellar granule cells, where it appears to be concentrated at the granule cell postsynaptic terminals. We also show that one form of NRG, Ig-NRG, plays a crucial role in aspects of cerebellar granule cell development in vitro. First, Ig-NRG treatment of granule cells in culture selectively induces the expression of the GABA(A) receptor beta2 subunit. This increase in subunit expression is paralleled by an increase in functional GABA(A) receptors. In contrast to its effects on GABA(A) receptor subunit expression, Ig-NRG does not upregulate NMDA receptor N2B and N2C subunit expression. Second, we demonstrate that Ig-NRG also enhances neurite outgrowth from cultured granule cells. Ig-NRG does not, however, act as a survival factor for the granule cells. We have compared the effect of Ig-NRG with the effects of brain-derived neurotrophic factor (BDNF), a neurotrophin that exerts specific effects on granule cells in culture, and found that BDNF does not mimic the effects of Ig-NRG on GABA(A) receptor subunit expression. Our results show that Ig-NRG has specific effects on granule cell development and maturation and may regulate these processes in vivo.

An Acute Effect of Neuregulin 1β to Suppress α7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons

“…NRG 1␤ induces expression of the GABA A receptor ␤2 subunit mRNA (Rieff et al, 1999;Xie et al, 2004) and NMDA receptor 2C subunit mRNA (Ozaki et al, Figure 7. NRG 1␤ increased ␣7 nAChR internalization in cultured hippocampal neurons.…”

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

“…17 NRG-1 also potentiates a7 nicotinic acetylcholine receptor transmission in hippocampal neurons, 20 and expression of the b2 subunit of the gamino butyric acid receptor in cerebellar granule cells. 19 Thus, the relative increase in type I expression in schizophrenia brain might alter neuronal signaling of NRG-1 per se, or it may be an indirect factor in putative abnormalities of NMDA, nicotinic, and/or GABA receptor-related signaling in schizophrenia brain. 21,32,33 The positive correlation between type I expression level and the daily dose of chlorpromazine equivalents suggests that this upregulation of type I could reflect a relationship between NRG-1 expression level and illness severity.…”

“…These NRG-1 isoforms play multiple and distinct functions in neuronal development, and abnormalities in brain development have been implicated in schizophrenia. Moreover, NRG-1 regulates the expression and plasticity of N-methyl-daspartate receptors (NMDAR), of the b2 subunit of the g-amino butyric acid receptor, and of nicotinic acetylcholine receptor subtypes including a5, a7, and b4 subunits [17][18][19][20] , some of which also may be involved in genetic risk for schizophrenia. 21,22 Thus, while genetic evidence implicates NRG-1 as a schizophrenia susceptibility gene, and the biology of NRG-1 overlaps with diverse aspects of the putative biology of schizophrenia, there have been no published studies of NRG-1 expression in the schizophrenic brain tissue, and little is known about whether a specific NRG-1 isoform contributes to the risk for schizophrenia.…”

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABACReceptors

“…A recent study indicates that Ig-neuregulin, a member of the epidermal growth factor superfamily that activates receptor tyrosine kinase, selectively increases GABA A receptor expression via induction of the ␤ 2 subunit (Rieff et al, 1999). Insulin, another growth factor well known to activate receptor tyrosine kinase, rapidly recruits GABA A receptors from the cytoplasmic to postsynaptic domains, increasing the amplitude of GABA A receptor-mediated mIPSC (Wan et al, 1997).…”