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SJTU Team Revealed Pyk2 as Novel Contextual Fear Memory Suppressor Molecule

September 30, 2021      Author:

On September 17, 2021, Wu Qiang's team from Shanghai Jiao Tong University had their latest research result titled "Pyk2 Suppresses Contextual Fear Memory in an Autophosphorylation-Independent Manner" published in the Journal of Molecular Cell Biology (JMCB). They discovered that Pyk2 can regulate gene expression, affect pyramidal neuronal complexity and spine dynamics, and suppress contextual fear memory in an autophosphorylation-independent manner.

The team used CRIPSR-Cas9 system to construct the Pyk2 gene deletion model in mice. Then through water maze experiment and conditional fear experiment, it was found that Pyk2 regulated the gene expression, the dynamic changes of dendrites and dendritic spines in an autophosphorylation-independent manner, and finally inhibited the contextual fear memory in mice. This study clarified the mechanism of Pyk2 in affecting contextual fear memory, enriched the regulatory network of learning and memory formation, and provided reference for further research on the pathological mechanism of mental diseases (such as Alzheimer's disease) and fear diseases (such as PTSD) associated with dysregulation of the Pcdh‒Pyk2 axis.

The molecular mechanism of Pyk2 suppressing scene-related fear memory

Zheng Jin, Ph.D. student of School of Life Science and Biotechnology, SJTU, is the first author of this research. Suo Lun, Zhou Yuxiao and Jia Liling of Systems Biomedicine Research Institute are the co-first authors. Wu Qiang and Suo Lun are the co-corresponding authors. The research was supported by the Ministry of Science and Technology, the Foundation of China and the Shanghai Science and Technology Commission.

 

Source: School of Life Science and Biotechnology

Translated by Zhou Rong

 

ABSTRACT:

Clustered protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion proteins that are central for neurite self-avoidance and neuronal connectivity in the brain. Their downstream non-receptor tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2, also known as Ptk2b, Cakb, Raftk, Fak2, and Cadtk) is predominantly expressed in the hippocampus. We constructed Pyk2 null mouse lines and found that these mutant mice showed enhancement in contextual fear memory, without any change in auditory-cued and spatial-referenced learning and memory. In addition, by preparing Y402F mutant mice, we observed that Pyk2 suppressed contextual fear memory. Moreover, using high-throughput RNA sequencing, we found that immediate early genes, such as Npas4, cFosZif268/Egr1Arc, and Nr4a1, were enhanced in Pyk2 null mice. We further showed that Pyk2 disruption affected . Thus, we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2 null mice provide a model for understanding fear-related disorders. These findings have interesting implications regarding dysregulation of the Pcdh‒Pyk2 axis in neuropsychiatric disorders.