As both NRG1 and ErbB4 have been linked to schizophrenia,...
As both NRG1 and ErbB4 have been linked to schizophrenia, the biological function of this signaling pathway in the CNS has been an area of intensive study. Recent studies indicate that NRG1-ErbB4 signaling may play an important role in the development of glutamatergic synapses (e.g., Fazzari et al., 2010). Since ErbB4 is highly expressed in a subset of GABAergic interneurons in the cortex and hippocampus, including parvalbumin (PV) positive interneurons, it is important to understand the role of NRG1-ErbB4 in synapse development specifically in GABAergic interneurons.
The recent study by Ting et al., a group led by Dr. Lin Mei in the Medical College of Georgia, provides new evidence that the NRG1-ErbB4 signaling pathway plays an important role in regulating the development and function of excitatory synapses in cortical and hippocampal GABAergic interneurons. By applying NRG1 to cultured neurons, they found that NRG1 increases the frequency and amplitude of miniature EPSCs, which is accompanied by an increase in the number and size of PSD-95 punctas, a marker of excitatory synapses. Furthermore, deletion of ErbB4 selectively in PV positive neurons causes a reduction of mEPSC frequency and amplitude in these neurons.
This study confirms and extends the major findings in the Fazzari et al., 2010 study, and they together make a strong case that NRG1-ErbB4 signaling is critical in regulating excitatory synapse maturation in GABAergic interneurons, and also suggest that NRG1-ErbB4 may regulate the wiring of cortical microcircuits during development. Given that both glutamatergic synapses and cortical GABAergic interneurons are thought to be involved in the pathophysiology of schizophrenia, the new findings by Ting and colleagues provide additional information for understanding the possible link between NRG1/ErbB4, synapses, and schizophrenia.
The recent study by Pitcher et al. provides a novel...
The recent study by Pitcher et al. provides a novel mechanism linking NRG1/ErbB4 activity to the suppression of NMDAR activity in a manner requiring Src kinase inhibition. The study uses biochemical manipulation of Src activation, as well as studies on cells lacking Src, to examine the role for Src kinase on the effects of NRG1 on NMDAR responses in pyramidal neurons. Overall, the study provides convincing evidence indicating that Src inhibition by NRG1 is an important contributor to the effects of NRG1 on NMDAR pyramidal neuronal hypofunction. The effect of NRG1 and ErbB4 on Src family kinase activation remains complex. Previous studies have found that NRG1 can activate Src, and that inhibition of Src family kinases can block some of the effects of NRG1 on cells, including cellular migration and proliferation (Eckert et al., 2009;
Grossmann et al., 2009). Moreover, ErbB4 activity is able to activate fyn when overexpressed in heterologous cells, and NRG1 treatment activates fyn in cells expressing endogenous ErbB4 (Bjarnadottir et al., 2007). Recent findings have similarly found that ErbB4 can activate Src kinases in heterologous cells and indicate that Src family kinase activation, particularly that of fyn, has a role in regulating the effects of NRG1 on interneuron morphology through RhoGEF activity (Cahill et al., 2011).
The findings of Picher et al. indicating that NRG1 can suppress Src kinase are not incompatible with these previously discussed studies, however. Indeed, studies have found that Src kinases can be both activated and inhibited by NRG1 treatment in a cyclic manner (Eckert et al., 2009), suggesting that the duration of NRG1 activity is an important consideration. The effects of NRG1 on pyramidal neuronal structure and/or function also seem to differ depending on the length of NRG1 treatment, as studies have found that chronic NRG1 or ErbB4 activity can promote synaptic structure and/or function (e.g., Barros et al., 2010; Li et al., 2007), whereas short-term NRG1 treatment is detrimental to pyramidal neuronal function (e.g., Wen et al., 2010), indicative of the importance of treatment duration to the functional consequences on neurons. The location of the examined effects is also an important consideration, as biochemical and morphological effects in pyramidal neurons and interneurons might differ following NRG1 treatment, potentially due to differences in ErbB4 expression profiles in these cells (Vullhorst et al., 2009). Given the links of NRG1/ErbB4 to schizophrenia, understanding how short-term and long-term activity of these molecules regulates both interneuron and pyramidal neuron function is of special importance, and merits further studies.
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PRIMARY NEWSNeuregulin and ErbB4: Synaptic Jacks of All Trades