| NRG1 is a member of a family of neurotrophic factors that acts by activating the tyrosine kinase of ErbB receptors, including ErbB4. In adult brains, Erbb4 mRNA is enriched in regions where interneurons are clustered. Furthermore, ErbB4 expression is largely confined to specific classes of interneurons, particularly parvalbumin (PV) cells, suggesting that PV interneurons are a major cellular target of NRG1-ErbB4 signaling in adult brain.Epilepsy is a disabling neurological disorder that affects about 1% of the general population of all ages. About 30% of affected individuals continue to have breakthrough seizures despite appropriate pharmacological anticonvulsant treatment, and surgical removal of the epileptic focus is suitable only for a minority. Understanding the causes of the pathology underlying the occurrence of seizures is necessary and urgent for finding effective and safe treatments.Fast-spiking interneurons expressing the calcium-binding protein parvalbumin, comprising 40-50% of GABAergic interneurons, are the dominant inhibitory system in neocortex. They preferentially project their axons onto the perisomatic region of target neurons, regulating the output of pyramidal neurons. Dysfunction of the fast-spiking interneurons is implicated in the pathogenesis of epilepsy. Thus, the causal link between reduced fast-spiking interneuron mediated inhibition and seizures has directed our efforts to counteract the loss of inhibition by increasing their activity.NRG1 regulates GABAergic transmission. In addition, recent studies demonstrate that ErbB4 in parvalbumin interneurons is critical for NRG1 regulation of pyramidal neuronal activity and long-term potentiation (LTP) in adult brain. All these studies suggest that parvalbumin interneurons are a major cellular target of NRG1-ErbB4 signaling in adult brain, and the causal link between reduced FS-PV intemeuron-mediated inhibition and seizures led us to hypothesize that dysfunction of NRG1-ErbB4 is involved in epilepsy.Here we investigated whether NRGl-ErbB4 directly regulates the excitability of FS-PV interneurons and the underlying mechanisms. Furthermore, we determined whether there is a link between down-regulated NRG1-ErbB4 signaling and epilepsy in adult brain. We found that NRG1, through its receptor ErbB4, increased the excitability of FS-PV interneurons. This effect was mediated by decreasing the voltage threshold through Kv1.1. Furthermore, mice with specific deletion of ErbB4 in parvalbumin interneurons were more susceptible to animal models of epilepsy. Expression of ErbB4 was also reduced in human epileptogenic tissue. Our findings suggest that ErbB4 may be a target for the development of a new class of anticonvulsant drugs.Mouse Model studies on seizures have demonstrated that Neuregulin-1/ErbB4 signaling is potentially involved in epilepsy. However, their biological significance in this disease itself remains to be evaluated. Neuregulinl and its receptor ErbB4 are highly reactive to changes in ambient neuronal activity in the rodent brain. Generation of epileptic seizures by using kainic acid or kindling elevated levels of Neuregulinl transcripts in cortical areas, hippocampus, and amygdala. Here we propose that patients with symptomatic epilepsy show a marked increase in protein levels of NRG1-ErbB4. Moreover, stimuli of NRG1-ErbB4 signaling suppressed the activity of Src activation, resulting inhibition of the phosphorylation level of GluN2B at 1472. And the Src-pY416/Src ratio and GluN2B-pY1472/GluN2B ratio is decreased in neocortex of symptomatic epileptic tissue. In addition, the structure and physiology of GABAergic function is presearved which is accordance with previous functional study in human epileptic study in neocortex.In summary, in combination with electrophysiological, genetic, biochemical and behavioral approach, we found that Neuregulin 1-ErbB4 signaling regulates the function of PV interneuron and contributes to epilepsy. |
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