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Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice
Published on: March 1, 2014
Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in
Xunyi Yan1, Bin Zhang1, Wen Lu1
1Department 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.
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.
Insights
Src homolog domain-containing phosphatase 2 (Shp2) knockout in neurons impairs memory by affecting NMDARs via Src, not ERK. Inhibiting Src rescues these cognitive deficits, revealing a novel pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- Src homolog domain-containing phosphatase 2 (Shp2) is crucial for cellular functions, including learning and memory.
- ERK signaling dysregulation, often linked to Shp2 mutations, causes cognitive deficits.
Purpose of the Study:
- To investigate the role of Shp2 in hippocampal pyramidal neurons on synaptic function and memory.
- To elucidate the specific signaling pathways (Src vs. ERK) involved in Shp2-mediated cognitive processes.
Main Methods:
- CaMKIIα-cre induced knockout (CaSKO) of Shp2 in mice.
- Assessed Src activity, NMDAR phosphorylation (GluN2A Y1325, GluN2B Y1472), synaptic transmission, and long-term potentiation.
- Utilized PP2, a Src family kinase inhibitor, to evaluate pathway-specific effects.
Main Results:
- CaSKO mice showed increased Src activity, elevated NMDAR phosphorylation, impaired synaptic transmission, and deficits in fear memory.
- PP2 administration reversed NMDAR phosphorylation, restored synaptic function, and rescued memory deficits without affecting ERK levels.
Conclusions:
- Shp2 plays a critical role in NMDAR-dependent synaptic plasticity and fear memory through the Src signaling pathway.
- Cognitive deficits associated with Shp2 are mediated by Src, not ERK, highlighting a complex regulatory mechanism.
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