Prolonged contextual fear memory in AMPA receptor palmitoylation-deficient mice

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2022-11, Vol.47 (12), p.2150-2159
• Main Authors: Oota-Ishigaki, Akiko, Takao, Keizo, Yamada, Daisuke, Sekiguchi, Masayuki, Itoh, Masayuki, Koshidata, Yumie, Abe, Manabu, Natsume, Rie, Kaneko, Masaki, Adachi, Toma, Kaizuka, Toshie, Suzuki, Nami, Sakimura, Kenji, Okuno, Hiroyuki, Wada, Keiji, Mishina, Masayoshi, Miyakawa, Tsuyoshi, Hayashi, Takashi
• Format: Article
• Language: English
• Subjects: Amygdala; Anxiety; Behavior; Epilepsy; Fear conditioning; Locomotion; Mental disorders; Mutation; Neural networks; Palmitoylation; Post traumatic stress disorder; Pyramidal cells; Seizures; Spatial discrimination learning; Spatial memory; Synaptic transmission; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-022-01347-9

Long-lasting fear-related disorders depend on the excessive retention of traumatic fear memory. We previously showed that the palmitoylation-dependent removal of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors prevents hyperexcitation-based epileptic seizures and that AMPA receptor palmitoylation maintains neural network stability. In this study, AMPA receptor subunit GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice were subjected to comprehensive behavioral battery tests to further examine whether the mutation causes other neuropsychiatric disease-like symptoms. The behavioral analyses revealed that palmitoylation-deficiency in GluA1 is responsible for characteristic prolonged contextual fear memory formation, whereas GluA1C811S mice showed no impairment of anxiety-like behaviors at the basal state. In addition, fear generalization gradually increased in these mutant mice without affecting their cued fear. Furthermore, fear extinction training by repeated exposure of mice to conditioned stimuli had little effect on GluA1C811S mice, which is in line with augmentation of synaptic transmission in pyramidal neurons in the basolateral amygdala. In contrast, locomotion, sociability, depression-related behaviors, and spatial learning and memory were unaffected by the GluA1 non-palmitoylation mutation. These results indicate that impairment of AMPA receptor palmitoylation specifically causes posttraumatic stress disorder (PTSD)-like symptoms.