title: Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in Forebrain Shp2-Deficient Mice.
abstract: Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Xunyi
authors: X
authors: Yan
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Bin
authors: B
authors: Zhang
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Wen
authors: W
authors: Lu
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Lin
authors: L
authors: Peng
authors: BIO-X Institute, Shanghai Jiaotong University, Shanghai, 200240, China.
authors: Qian
authors: Q
authors: Yang
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Wei
authors: W
authors: Cao
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Shen
authors: S
authors: Lin
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Wenyue
authors: W
authors: Yu
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Xiaoming
authors: X
authors: Li
authors: Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors: Yuehai
authors: Y
authors: Ke
authors: BIO-X Institute, Shanghai Jiaotong University, Shanghai, 200240, China.
authors: Shengtian
authors: S
authors: Li
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China. yangwei@zju.edu.cn.
authors: Wei
authors: W
authors: Yang
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China. luojianhong@zju.edu.cn.
authors: Jianhong
authors: http://orcid.org/0000-0001-7832-496X
authors: J
authors: Luo
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency*; D011743:Pyrimidines / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D019061:src-Family Kinases
chemical_list: C412373:AG 1879; D011743:Pyrimidines; D019061:src-Family Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: LTP; Memory; NMDAR; Shp2; Src