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Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory

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Abstract

Hippocampal function is important for learning and memory, and dysfunction of the hippocampus has been linked to the pathophysiology of neuropsychiatric diseases such as schizophrenia. Neuregulin1 (NRG1) and ErbB4, two susceptibility genes for schizophrenia, reportedly modulate long-term potentiation (LTP) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, little is known regarding the contribution of hippocampal NRG1/ErbB4 signaling to learning and memory function. Here, quantitative real-time PCR and Western blotting were used to assess the mRNA and protein levels of NRG1 and ErbB4. Pharmacological and genetic approaches were used to manipulate NRG1/ErbB4 signaling, following which learning and memory behaviors were evaluated using the Morris water maze, Y-maze test, and the novel object recognition test. Spatial learning was found to reduce hippocampal NRG1 and ErbB4 expression. The blockade of NRG1/ErbB4 signaling in hippocampal CA1, either by neutralizing endogenous NRG1 or inhibiting/ablating ErbB4 receptor activity, enhanced hippocampus-dependent spatial learning, spatial working memory, and novel object recognition memory. Accordingly, administration of exogenous NRG1 impaired those functions. More importantly, the specific ablation of ErbB4 in parvalbumin interneurons also improved learning and memory performance. The manipulation of NRG1/ErbB4 signaling in the present study revealed that NRG1/ErbB4 activity in the hippocampus is critical for learning and memory. These findings might provide novel insights on the pathophysiological mechanisms of schizophrenia and a new target for the treatment of Alzheimer’s disease, which is characterized by a progressive decline in cognitive function.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grants 81329003; U1201225; 31430032), Guangzhou Science and Technology Project (grant 201300000093), and Specialized Research Fund for the Doctoral Program of Higher Education of China (grant 20134433130002).

Author Contributions

Tian-Ming Gao designed the study, contributed to preparation of the manuscript, and supervised all aspects of the study. Jia Tian contributed to the design of the study, experiment performance, data analysis, and preparation of the manuscript. Fei Geng, Yi-Hua Chen, Ji-Hong Liu, Jian-Lin Wu, Yu-Jie Lan, Feng Gao, and Yuan-Ning Zeng did the experiment. Xiao-Wen Li and Jian-Ming Yang contributed to preparation of the manuscript. All authors have approved the final manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 1023S Shatai Road, Guangzhou, 510515, China

    Jia Tian, Fei Geng, Feng Gao, Yi-Hua Chen, Ji-Hong Liu, Jian-Lin Wu, Yu-Jie Lan, Yuan-Ning Zeng, Xiao-Wen Li, Jian-Ming Yang & Tian-Ming Gao

  2. College of Biological Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China

    Jia Tian

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  1. Jia Tian
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Tian, J., Geng, F., Gao, F. et al. Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory. Mol Neurobiol 54, 3976–3987 (2017). https://doi.org/10.1007/s12035-016-9956-5

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