Altered NMDA receptor trafficking contributes to sleep deprivation-induced hippocampal synaptic and cognitive impairments Chu Chen a, * , Mattie Hardy a , Jian Zhang a , Gerald J. LaHoste b , Nicolas G. Bazan a, * a Neuroscience Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA b Department of Psychology, University of New Orleans, New Orleans, LA 70148, USA Received 29 November 2005 Available online 15 December 2005 Abstract Recent evidence indicates that continuous wakefulness (sleep deprivation, SD) causes impairments in behavioral performance and hippocampal long-term potentiation (LTP) in animals. However, the mechanisms by which SD impairs long-term synaptic plasticity and cognitive function are not clear. Here, we report that 24-h SD in mice results in impaired hippocampus-dependent contextual mem- ory and LTP and, unexpectedly, in reductions of the surface expression of NMDA receptor (NMDAR) subunit NR1 and NMDAR- mediated excitatory post-synaptic currents at hippocampal perforant path-dentate granule cell synapses. The results suggest that the reduction of functional NMDAR in hippocampal neurons may underlie the SD-induced deficits in hippocampus-dependent contextual memory and long-term synaptic plasticity. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Long-term potentiation; Rapid eye movement sleep; Hippocampus-dependent contextual memory Sleep deprivation (SD) is usually defined as depriving a person or organism of sleep for periods of varying dura- tion. Humans frequently encounter situations that disrupt the normal sleep/wakefulness pattern, and inadequate sleep impairs memory of recent events and attention to ongoing activities. Although the function of sleep remains unknown, it has been proposed that there are a number of necessary neurobiological, physiological, and behavioral processes occurring throughout the brain and body during sleep [1,2]. Prolonged and complete sleep loss impairs temperature control, digestive metabolism, and immune function, and leads ultimately to death. Accumulated evi- dence from behavioral, physiological, and cellular and molecular studies suggests that sleep is crucial to learning and memory [3–14]. SD is prevalent in various occupations and individuals: shift workers who change shifts, military personnel in training exercises and under combat condi- tions, medical personnel, children who do not have regular sleep cycles, and individuals with sleep disorders. For instance, recent studies show that interns who had extend- ed work shifts made more serious medical errors and had increased attention failure when compared to those with reduced work hours [15,16]. This means that sleep loss induces neurocognitive deficits. We have found recently that continuous wakefulness for 72 h in rats causes severe behavioral, synaptic, and membrane excitability alterations in the hippocampus [9]. However, mechanisms by which SD induces deficits in synaptic plasticity and memory for- mation are still unknown. While LTP at both perforant path and CA3-CA1 synapses is reduced in SD rats, changes in membrane properties (e.g., input resistance and firing properties) are different in dentate granule neurons and CA1 pyramidal neurons [9]. The membrane excitability is reduced in CA1 pyramidal neurons, but it remains intact in dentate granule neurons in SD rats, suggesting that the alteration in membrane excitability in SD animals may not be fully responsible for the reduced synaptic plasticity. 0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.12.021 * Corresponding authors. Fax: +1 504 599 0488. E-mail addresses: cchen@lsuhsc.edu (C. Chen), nbazan@lsuhsc.edu (N.G. Bazan). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 340 (2006) 435–440 BBRC