Abstract
BackgroundNeuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. NMDARs also promote many cellular events such as proliferation and survival of neuroblasts before synapse formation. Although many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied.ResultsNRG1 induces activation of NMDAR subunit NR2B, and tropomyosin-related kinase receptor B (TrkB), the receptor for BDNF via activation of phospholipase C-gamma (PLC-γ) in immature primary cortical neurons. Our data using TrkB inhibitor (K252a), TrkB siRNA and TrkB−/− neurons demonstrated that TrkB inhibition suppresses NRG1-induced NR2B activation in neurons. We found that NRG1 stimulation leads to GABAA receptor-mediated TrkB activation. Co-immunoprecipitation and proximity ligase assay showed that TrkB interacts with ErbB4 (NRG1 receptor) and the TrkB-ErbB4 interaction was increased following NRG1 treatment. A significant reduction in TrkB-ErbB4 interaction was observed in the prefrontal cortex of schizophrenia subjects. We found significant increase in released BDNF levels following NRG1 treatment, which was inhibited by ErbB4 inhibitor, AG1478. In addition, pretreatment with BDNF neutralizing antibody, but not control IgG abolished NRG1-induced increases in phospho-TrkB and phospho-NR2B levels. Moreover, studies using TrkB mutants showed that intercellular domain of TrkB is necessary for TrkB-ErbB4 interaction and NR2B activation.ConclusionsBDNF/TrkB signaling plays an important role in the NRG1-stimulated NR2B regulation. These findings could be of relevance to many neurodevelopmental disorders, as NRG1 and BDNF signaling pathways have been implicated in autism and schizophrenia.
Highlights
Activation of NMDA type glutamate receptors (NMDARs) facilitate a number of signaling pathways involved in neuronal development, learning, and memory [1]
tropomyosin-related kinase receptor B (TrkB) inhibition suppresses Neuregulin 1 (NRG1)-induced NR2B phosphorylation in primary cortical neurons We first determined the effect of NRG1 on the activation of ErbB4, TrkB and NR2B in dissociated cortical neurons before synapses are formed (DIV 4) [19]
We found a significant inhibition on NRG1-induced Brain derived neurotrophic factor (BDNF) release (Figure 2Ci) as well as TrkB phosphorylation (Figure 2E) in neurons pretreated with picrotoxin, a GABAA receptor antagonist
Summary
Activation of NMDA type glutamate receptors (NMDARs) facilitate a number of signaling pathways involved in neuronal development, learning, and memory [1]. Prior to synapse formation, activation of NMDARs promotes many cellular events including proliferation and survival of neuroblasts [4]. Recent studies have found the role of NRG1 in the regulation of glutamatergic signaling; in particular NR2B function [7,8,9]. NRG1 has been shown to promote excitatory synapse development in GABAergic interneurons [11] These studies indicate that the effect of NRG1 on NR2B function in neurons prior to synapse formation needs further investigation. Neuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. Many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied
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