On Dec 11, 2011, Nature Neuroscience published online a full original article from Dr. Zhi-Qi Xiong’s laboratory entitled “Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons”. This work was carried out by graduate students Guo-He Tan and Yuan-Yuan Liu etc, in collaboration with Dr. Lin Mei’s laboratory from Georgia Health Sciences University.

Activity-dependent expression of polypeptide growth factors has been implicated in epileptogenesis, such as brain-derived neurotrophic factor (BDNF) which was shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counter-balancing mechanisms. In this study, Tan et al report a critical role of Neuregulin 1, and its signaling in limbic epileptogenesis. The authors found that the signaling is responsive to and up-regulated by seizure activity. Limbic epileptogenesis was inhibited by intracerebral infusion of recombinant Neuregulin 1, but markedly exacerbated by scavenging endogenous Neuregulin 1 with soluble ErbB4 extracellular domain (ecto-ErbB4), or by inhibiting ErbB4 activation with PD158780, or by deleting the Erbb4 gene. They further employed Cre-loxP-mediated cell-specific knockout to identify the specific cellular mechanism underlying the anti-epileptogenic effect of Neuregulin 1 signaling. Selective depletion of ErbB4 in parvalbumin-expressing interneurons abolished Neuregulin 1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased kindling-induced brain hyperexcitability, spontaneous seizures and exuberant mossy fiber sprouting — a chronic pathological feature of limbic epilepsy. In contrast, depleting ErbB4 in CaMKIIα-expressing pyramidal neurons was ineffective for epileptogenesis. Thus, these findings identify Neuregulin 1 as a previously unrecognized suppressor in the pathogenic process of limbic epilepsy and suggested that activity-dependent NRG1 activation of ErbB4 receptor in parvalbumin-expressing interneurons serves as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.

This work was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology, the National Natural Science Foundation of China to Z.Q.X and from the US National Institutes of Health to L.M.

Figure. A small molecule (yellow bulbs), neuregulin 1, is released from principle neurons (red cell) in the brain during seizure, and activates its receptor ErbB4 in a subset of interneurons (green cell) selectively to inhibit epileptogenesis, thus acting as an endogenous negative-feedback signaling for mitigating the excessive neuronal network activity of limbic epilepsy.