Research reportShort-term sleep deprivation disrupts the molecular composition of ionotropic glutamate receptors in entorhinal cortex and impairs the rat spatial reference memory
Introduction
Sleep serves a vital function in metabolic homeostasis, learning-related synapse formation and neuronal reactivation, which is indispensable for the memory formation [1], [2], [3], [4], [5]. Numerous studies reported that sleep deprivation (SD) causes impairment in the cognitive performance, especially about the spatial learning and memory. Acute or chronic SD has been reported to affect neuronal function [6] and cause deficits in the acquisition and consolidation of spatial reference memory in Morris water maze [7], [8], [9], [10], [11]. In addition, SD impaired the spatial working memory in radial maze [12], T-maze [13] and novel arm recognition tasks [14].
Entorhinal cortex (EC) plays a crucial role in spatial learning and memory [15], [16], [17]. Anatomically, it is an interface that mediates the dialogue between hippocampus and neocortex [18], [19]. Moreover, EC contains spatially modulated neurons such as grid cells and border cells, and actively participates in spatial information processing [20], [21], [22]. Previous studies found that the neurotransmitter receptors in EC are sensitive to SD. Paradoxical SD with 96 h caused a downregulation of the M2-type cholinergic receptors [23], while the D1 receptor binding was selectively increased in the EC of SD rats [24].
Among the neurotransmitter receptors, the ionotropic glutamate receptors, especially the 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-d-aspartate receptors (NMDARs), mediate the basic excitatory synaptic transmission, and are critical for formation of grid cells in EC and the related spatial cognition [25], [26], [27], [28]. AMPARs and NMDARs function as tetramers that are assembled from GluA1-4 and GluN1-3, respectively [25]. In parallel with the SD-induced changes in cognitive function, AMPARs and NMDARs have been reported to be vulnerable to SD in neocortex and hippocampus. A brief or chronic SD has been reported to alter the AMPARs and NMDARs, especially their subunit expression levels, in these brain regions [13], [29], [30], [31].
Although the numerous studies have concerned the influence of SD on the hippocampal and cortical AMPARs and NMDARs, whether and how SD affects these subunit expression in the EC remains unexplored. To fully grasp the effects of the SD in spatial memory circuitry, the present study focused on EC and conducted western blotting experiments to systematically detect the effects of SD with short duration (4 h) that frequently occurs in our daily life on the total and surface expressions of AMPAR and NMDAR subunits. Our findings suggest that brief SD disrupted the molecule composition of the AMPARs and NMDARs in EC, which might partially underlie the SD-induced deficits in spatial cognition.
Section snippets
Animal
Male Sprague-Dawley rats weighting 140 ± 20 g were used in the present study. Rats were housed in a Plexiglas cages (four per cage), with a 12:12 light–dark cycle (lights on at 8:00 a.m.) and with food and water available ad libitum. Room temperature was controlled at 22 ± 1°C.
Sleep deprivation
In the present study, eight animals were randomly divided into control and SD groups. The method for total SD is consistent with that of previous studies [2], [13], [32]. Briefly, the experimenter introduces novel objects into
The surface, instead of total, expression levels of AMPAR subunits were affected by 4 h SD
The EC is regarded as the gateway of the hippocampus and plays an important role in episodic memory, especially spatial memory [16], [18]. Here, we first examined effects of SD on EC AMPAR subunit expression. After 4 h of SD, surface expression levels of GluA1 (71.0 ± 12.0%) was reduced, while surface expression of GluA2 (125.0 ± 8.0%) and GluA3 (146.0 ± 16.0%) were significantly increased (Fig. 1a). The total expressions of these AMPARs were not affected by SD (Fig. 1b). Then the ratio of surface to
Discussion
The present study for the first time, to the best of our knowledge, symmetrically investigated the influence of short-term SD on the AMPAR and NMDAR subunit expression in the EC, which is the ‘hub’ between neocortex and hippocampus and serves a vital role in spatial cognition [16], [18], [22], [35], [36]. We found 4 h SD differently affected the AMPAR subunit surface expression primarily via influencing their membrane trafficking. Moreover, short-term SD reduced the surface expression levels of
Acknowledgment
This work was supported by grant from the National Natural Science Foundation of China (No. 81301137).
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A brief period of sleep deprivation negatively impacts the acquisition, consolidation, and retrieval of object-location memories
2020, Neurobiology of Learning and MemoryCitation Excerpt :Nevertheless, 4 h of SD directly before the retention trial of the MWM did increase surface expression levels of GluN1 and GluN2B with no effect on GluN2A (Xie et al., 2016). The AMPARs, on the other hand, do seem to be affected as 4 h of SD directly before the retention trial of the MWM strongly reduced surface expression of GluA1, while simultaneously increasing GluA2 and GluA3 levels (Xie et al., 2016). Whether these effects are mediated through cAMP signaling remains to be seen.
Dopamine type 1- and 2-like signaling in the modulation of spatial reference learning and memory
2019, Behavioural Brain ResearchCitation Excerpt :For instance, the negative correlation of the glutamate receptor 1 (GRIA 1) adjustment of glutamate receptors related to learning and memory processes. Regulation of AMPAR and NMDAR composition in the entorhinal cortex by sleep deprivation has been found to affect reference memory in the water maze in rats [42]. Generally, the regulation of glutamate receptor subunits and glutamate metabolism related proteins point to synaptic changes in adjustment with other brain regions involved in spatial long-term memory like the HPC [43,44].
Transcranial near-infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep-deprived mice
2018, Brain ResearchCitation Excerpt :Numerous animal and clinical studies have shown a strong correlation between sleep restriction and impaired cognitive function, including memory and learning (Graves et al., 2001; Mahmoudi et al., 2017; Meerlo et al., 2009). Sleep deprivation disrupts cognitive performance in individuals (Durmer and Dinges, 2005) and in animal models causes memory impairment in different cognitive tasks (Alzoubi et al., 2017a; Azogu et al., 2015; Smith et al., 1998; Xie et al., 2016). Although the precise underlying mechanisms responsible for cognitive impairment induced by sleep deprivation remain elusive, hippocampal mitochondrial dysfunction (particularly impaired complex IV activity and elevated oxidative stress) have been suggested as important factors (Chanana and Kumar, 2017; Villafuerte et al., 2015).
Sleep deprivation decreases neuronal excitability and responsiveness in rats both in vivo and ex vivo
2018, Brain Research BulletinCitation Excerpt :Surface level of GluA2, GluA3 and GABAAR in the hippocampus was significantly up-regulated after 8 h sleep-deprived rats compared to the 4 h sleep-deprived rats indicating that sleep loss altered the relative expression levels of the AMPA- and NMDA type receptors (Xie et al., 2015). However, it was also proved, that GluA1, GluN1 and GluN2B levels were decreased in the synapses (Xie et al., 2016). Taken together, it can be hypothesized that during the relatively long sleep deprivation (6 h) used in the present study, in parallel with the decreasing glutamate level toward the end of sleep deprivation, different changes developed in the expression of AMPA and NMDA receptor subunits.
Sleep loss and structural plasticity
2017, Current Opinion in NeurobiologyCitation Excerpt :In flies, sleep loss appears to increase NMDAR activity and intracellular Ca2+ in specific circuits, which not only increases presynaptic puncta number and size, but could also explain increased neuronal excitability [10••,28]. In rodents, acute sleep loss changes NMDAR in a manner that decreases their Ca2+ permeability (i.e., predominance of NR2A over NR2B) in both the hippocampus and cerebral cortex [26,27], which likely contributes to decreased phosphorylation of Ca2+/calmodulin-dependent kinase II (CamKII) [29] (Figure 2), a mechanism that can negatively regulate spine size [30]. In parallel, structural synaptic changes implicate signaling that impact the protein synthesis machinery [31], and sleep loss was shown to affect mammalian target of rapamycin (mTOR)-dependent protein synthesis [32,33], and to consequently impair sleep-regulated functions [34].