DHHC2 regulates fear memory formation, LTP, and AKAP150 signaling in the hippocampus

Meng-Die Li; Lu Wang; Yu-Qi Zheng; Dan-Hong Huang; Zhi-Xuan Xia; Jian-Min Liu; Dan Tian; Hui OuYang; Zi-Hao Wang; Zhen Huang; Xiao-Shan Lin; Xiao-Qian Zhu; Si-Ying Wang; Wei-Kai Chen; Shao-Wei Yang; Yue-Ling Zhao; Jia-An Liu; Zu-Cheng Shen

doi:10.1016/j.isci.2023.107561

DHHC2 regulates fear memory formation, LTP, and AKAP150 signaling in the hippocampus

iScience. 2023 Aug 9;26(9):107561. doi: 10.1016/j.isci.2023.107561. eCollection 2023 Sep 15.

Authors

Meng-Die Li¹, Lu Wang², Yu-Qi Zheng¹, Dan-Hong Huang¹, Zhi-Xuan Xia³, Jian-Min Liu⁴, Dan Tian¹, Hui OuYang¹, Zi-Hao Wang⁵, Zhen Huang¹, Xiao-Shan Lin¹, Xiao-Qian Zhu¹, Si-Ying Wang¹, Wei-Kai Chen¹, Shao-Wei Yang¹, Yue-Ling Zhao¹, Jia-An Liu⁶, Zu-Cheng Shen¹

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
² Department of Nephrology, Fuzhou Children's Hospital of Fujian Province, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China.
³ Department of Pharmacology, School of Basic Medicine and Life Science, Hainan Medical University, Haikou 571199, China.
⁴ Department of Pharmacy, Wuhan No. 1 Hospital, Wuhan 430000, China.
⁵ Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
⁶ Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.

Abstract

Palmitoyl acyltransferases (PATs) have been suggested to be involved in learning and memory. However, the underlying mechanisms have not yet been fully elucidated. Here, we found that the activity of DHHC2 was upregulated in the hippocampus after fear conditioning, and DHHC2 knockdown impaired fear induced memory and long-term potentiation (LTP). Additionally, the activity of DHHC2 and its synaptic expression were increased after high frequency stimulation (HFS) or glycine treatment. Importantly, fear learning selectively augmented the palmitoylation level of AKAP150, not PSD-95, and this effect was abolished by DHHC2 knockdown. Furthermore, 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150 and the interaction between AKAP150 and PSD-95 induced by HFS. Lastly, DHHC2 knockdown reduced the phosphorylation level of GluA1 at Ser845, and also induced an impairment of LTP in the hippocampus. Our results suggest that DHHC2 plays a critical role in regulating fear memory via AKAP150 signaling.

Keywords: Biochemistry; Molecular biology; Neuroscience.