APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

• Published in: The Journal of neuroscience 2022-03, Vol.42 (13), p.2662-2677
• Main Authors: Shen, Zu-Cheng, Xia, Zhi-Xuan, Liu, Jian-Min, Zheng, Jie-Yan, Luo, Yu-Fei, Yang, Han, Li, Meng-Die, Cao, Ting, Liu, Hai-Ping, Jin, Gui-Lin, Huang, Hui-Hui, Yu, Chang-Xi, Zhou, Jun
• Format: Article
• Language: English
• Subjects: Aging; Animals; Biotin; Biotinylation; Cognitive ability; Density; Fear; Fear conditioning; Glutamatergic transmission; Glutamic acid receptors; Hippocampal plasticity; Hippocampus; Hippocampus - metabolism; Hydroxylamine; Learning; Localization; Memory; Mental disorders; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Palmitoyl-(protein) hydrolase; Palmitoylation; Plasticity; Post traumatic stress disorder; Postsynapse; Postsynaptic density proteins; Proteins; Psychological stress; Rats; Receptors; Synapses - metabolism; Synaptic plasticity; Synaptic strength; Synaptic transmission; Synaptic Transmission - physiology; Thioesterase; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1741-21.2022

Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders. Fear-related anxiety disorders, including post-traumatic stress disorder, are prevalent psychiatric conditions, and fear memory is associated with hyperexcitability in the hippocampal CA1 region. Palmitoylation is involved in learning and memory, but mechanisms coupling palmitoylation with fear memory acquisition remain poorly understood. This study demonstrated that palmitoylation is essential for postsynapse density-95 clustering and hippocampal glutamatergic synaptic transmission, and APT1-mediated depalmitoylation plays crit