ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation

Yong Jun Chen, Meng Zhang, Dong Min Yin, Lei Wen, Annie Ting, Pu Wang, Yi Sheng Lu, Xin Hong Zhu, Shu Ji Li, Cui Ying Wu, Xue Ming Wang, Cary Lai, Wen Cheng Xiong, Lin Mei, Tian Ming Gao

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Abstract

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABAA receptormediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABAA receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4-/- mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre; ErbB4-/- hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4-/- mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.

Original languageEnglish (US)
Pages (from-to)21818-21823
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number50
DOIs
StatePublished - Dec 14 2010

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Chen, Y. J., Zhang, M., Yin, D. M., Wen, L., Ting, A., Wang, P., Lu, Y. S., Zhu, X. H., Li, S. J., Wu, C. Y., Wang, X. M., Lai, C., Xiong, W. C., Mei, L., & Gao, T. M. (2010). ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21818-21823. https://doi.org/10.1073/pnas.1010669107