Sleep loss or insomnia is among the contributing factors of cognitive deficit, the underlying mechanisms of which remain largely elusive. The endocannabinoid (eCB) system plays a role in sleep, while it is unknown if it is involved in the regulation of memory retrieval by sleep deprivation. In addition, it still controversial how rapid-eye-movement sleep deprivation (REMSD) affects the spatial memory of adolescent mice. Here, we found that 24-h REMSD impairs spatial memory retrieval of adolescent mice in an object-place recognition task, which was rescued by NESS0327, a neutral cannabinoid receptor 1 (CB1R) antagonist. Mechanistically, REMSD induced eCB-mediated short-term and long-term synaptic plasticity changing including depolarization-induced suppression of inhibition (DS!) in the pyramidal neurons of the hippocampus, in which long-term synaptic plasticity changing was rescued by NESS0327. REMSD downregulated monoacylglycerol lipase, a hydrolase for the endocannabinoid 2-arachidonoylglycerol (2-AG), suggesting the involvement of eCB accumulation and the consequent synaptic plasticity in REMSD-elicited memory impairment in adolescent mice. These findings shed light on the role of sleep disorders in learning and memory deficit of adolescents. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.