Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory.
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.
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.|College of Biological Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China.
Jia
J
Tian
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.
Fei
F
Geng
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.
Feng
F
Gao
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.
Yi-Hua
YH
Chen
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.
Ji-Hong
JH
Liu
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.
Jian-Lin
JL
Wu
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.
Yu-Jie
YJ
Lan
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.
Yuan-Ning
YN
Zeng
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.
Xiao-Wen
XW
Li
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.
Jian-Ming
JM
Yang
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. tgao@smu.edu.cn.
Tian-Ming
TM
Gao
D000818:Animals; D015536:Down-Regulation; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008568:Memory; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D065853:Spatial Learning
D020890:Neuregulin-1; D010320:Parvalbumins; D012333:RNA, Messenger; D066247:Receptor, ErbB-4
ErbB4; Hippocampus; Learning; Memory; NRG1; Parvalbumin interneurons