TY - JOUR
T1 - The facilitating effect of MK-801 on inhibitory avoidance memory via mTOR signaling in the mouse hippocampus
AU - Hsiung, Ming Heng
AU - Huang, Wan Ling
AU - Kan, Li Yu
AU - Chen, Li Hsien
AU - Hu, Sherry Shu Jung
N1 - Funding Information:
This work was supported by ROC Ministry of Science and Technology (MOST) grant Nos. 104-2410-H-006-025-MY3, 105-2410-H-006-019-MY2, and 107-2410-H-006-056- to SSH.
Funding Information:
This work was supported by ROC Ministry of Science and Technology (MOST) grant Nos. 104-2410-H-006-025-MY3 , 105-2410-H-006-019-MY2 , and 107-2410-H-006-056- to SSH.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Despite the widespread belief that MK-801 induces memory deficits associated with dementia and schizophrenia in animal models, data regarding the impairing effect of MK-801 on aversive memory have been inconclusive. In this study, we investigated the effect of MK-801 on multiple memory stages of the inhibitory avoidance task, as well as its underlying signaling mechanism in the mouse hippocampus. We successfully replicated a previous finding suggesting that systemic injection of MK-801 impaired memory acquisition, but we observed that an intrahippocampal infusion of MK-801 facilitated the same memory process. We also found that both systemic and intrahippocampal administration of MK-801 facilitated memory consolidation and memory retrieval of the inhibitory avoidance task. We demonstrated that MK-801-induced increases in shock sensitivity and locomotor activity in the pre-training regimen confounded the detrimental effect of MK-801 on memory acquisition, thereby reconciling the inconsistent results in previous studies. In addition, the memory-facilitating effect of MK-801 was found to be dependent on drug dose and shock intensity. We next showed that MK-801 induced a fast-onset increase in the extent of mammalian target of rapamycin (mTOR) phosphorylation in the hippocampus. Finally, we observed that rapamycin, an mTOR inhibitor, blocked both the MK-801-induced increases in phosphorylated mTOR and the facilitating effect of MK-801 on memory consolidation. These results indicate that hippocampal mTOR signaling mediates the facilitating effect of MK-801 on memory consolidation of the inhibitory avoidance task. These findings further imply that MK-801 indeed functions as a memory enhancer and that mTOR signaling serves as a therapeutic target for memory disorders.
AB - Despite the widespread belief that MK-801 induces memory deficits associated with dementia and schizophrenia in animal models, data regarding the impairing effect of MK-801 on aversive memory have been inconclusive. In this study, we investigated the effect of MK-801 on multiple memory stages of the inhibitory avoidance task, as well as its underlying signaling mechanism in the mouse hippocampus. We successfully replicated a previous finding suggesting that systemic injection of MK-801 impaired memory acquisition, but we observed that an intrahippocampal infusion of MK-801 facilitated the same memory process. We also found that both systemic and intrahippocampal administration of MK-801 facilitated memory consolidation and memory retrieval of the inhibitory avoidance task. We demonstrated that MK-801-induced increases in shock sensitivity and locomotor activity in the pre-training regimen confounded the detrimental effect of MK-801 on memory acquisition, thereby reconciling the inconsistent results in previous studies. In addition, the memory-facilitating effect of MK-801 was found to be dependent on drug dose and shock intensity. We next showed that MK-801 induced a fast-onset increase in the extent of mammalian target of rapamycin (mTOR) phosphorylation in the hippocampus. Finally, we observed that rapamycin, an mTOR inhibitor, blocked both the MK-801-induced increases in phosphorylated mTOR and the facilitating effect of MK-801 on memory consolidation. These results indicate that hippocampal mTOR signaling mediates the facilitating effect of MK-801 on memory consolidation of the inhibitory avoidance task. These findings further imply that MK-801 indeed functions as a memory enhancer and that mTOR signaling serves as a therapeutic target for memory disorders.
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U2 - 10.1016/j.bbr.2020.112630
DO - 10.1016/j.bbr.2020.112630
M3 - Article
C2 - 32348869
AN - SCOPUS:85084521444
SN - 0166-4328
VL - 389
JO - Behavioural Brain Research
JF - Behavioural Brain Research
M1 - 112630
ER -