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Objective Epilepsy is a common and refractory neurological disorder that affects 1%-2% worldwide people, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear.Activity-dependent expression of polypeptide growth factors has been implicated in epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counter-balancing mechanisms.In this study, we investigated the role of a growth factor neuregulin 1 (NRG1) and its ErbB4 receptor in limbic epileptogenesis.Methods Two classical models of limbic epilepsy, kindling and pilocarpine models, were used to investigate the expression pattern of NRG1 and ErbB4.Using lose-and gain-of-function strategies, we determined the role of NRG1/ErbB4 signaling in epileptogenesis pharmacologically and genetically.Cre/loxP-mediated cell-specific mutation was employed to identify the specific cellular mechanism underlying the effect of this signaling in limbic epileptogenesis.Results (1) Limbic seizure activity increased the expression of Nrgl and phosphorylation of ErbB4 receptor in the brain.(2) In kindling model, epileptogenesis was inhibited by intracerebral infusion of recombinant NRG1, but exacerbated by neutralizing endogenous NRG1 with soluble ecto-ErbB4.(3) Pharmacologically, inhibition of ErbB4 activity with PD158780 greatly promoted kindling-induced epileptogenesis.(4) Genetically, heart-rescued ErbB4 knockout mice exhibited accelerated progression of the kindling effect.(5) Specific depletion of ErbB4 in parvalbumin (PV)-positive GABAergic interneurons resulted in accelerated kindling development.Importantly, NRG1 infusion failed to suppress kindling development in PV-Cre;ErbB4-/-mice.(6) Deletion of ErbB4 in CaMKⅡα-positive pyramidal neurons was ineffective for epileptogenesis, as evidenced by normal kindling progression of both CaMKⅡα-iCre;ErbB4-/-and CaMKⅡα-CreER;ErbB4-、-mice.(7) Ablation of ErbB4 in PV-positive neurons increased kindling-induced brain hyperexcitability and spontaneous seizures.(8) Pharmacological alternation of NRG 1/ErbB4 signaling affected seizure-induced mossy fiber sprouting, a chronic pathological feature of limbic epilepsy.Furthermore, both heart-rescued ErbB4 mutant mice and PV-Cre;ErbB4-/-mice exhibited exuberant mossy fiber sprouting after kindling.Conclusion This study identified NRG1 as a previously unrecognized suppressor in pathogenic process of limbic epilepsy and suggested that activity-dependent NRG1/ErbB4 signaling in PV-positive interneurons serves as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis, providing a novel potential target for the treatment of epilepsy.