title: ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation.
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 GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) 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.
authors.affiliation: Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.forename: Lei
authors.initials: L
authors.lastname: Wen
authors.forename: Annie
authors.initials: A
authors.lastname: Ting
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Lu
authors.forename: Xin-Hong
authors.initials: XH
authors.lastname: Zhu
authors.forename: Shu-Ji
authors.initials: SJ
authors.lastname: Li
authors.forename: Cui-Ying
authors.initials: CY
authors.lastname: Wu
authors.forename: Xue-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Cary
authors.initials: C
authors.lastname: Lai
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Tian-Ming
authors.initials: TM
authors.lastname: Gao
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005239:Fear; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007395:Interneurons / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D066247:Receptor, ErbB-4; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D058787:GABA-A Receptor Antagonists; D020890:Neuregulin-1; D010320:Parvalbumins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4