Women are usually at risk
Women are usually at risk of sleep deprivation or restriction during pregnancy, especially in the third trimester of gestation, due to the pregnancy-associated anatomic, physiological and hormonal changes (Pien and Schwab, 2004). However, several major SAR405838 developmental events, such as the neuronal circuit development in the hippocampus, amygdala and cerebral cortex, occur during the final stages of gestation in rats (Charil et al., 2010, Clancy et al., 2001). Therefore, MSD during the last trimester of pregnancy results in a herd of disabilities in both the mother and the offspring. For instance, maternal sleep deprivation decreases the reproductive capability of the offspring, (especially the male offspring (Alvarenga et al., 2013)) affects morphometry and cardiovascular functions of offspring (Raji, 2015), and even impairs the hippocampal neurogenesis and cognition of offspring (Zhao et al., 2014, Zhao et al., 2015). In full agreement with these findings, we present new evidence here that MSD during the last trimester of pregnancy dramatically impairs hippocampus-dependent spatial learning and memory (Fig. 3), and increases anxiety (Fig. 4) and depressive-like behaviors in the offspring (Fig. 5). Synaptic plasticity, particularly LTP and LTD in the hippocampus, has been proposed to be a biological substrate for at least some forms of learning and memory (Bliss and Collingridge, 1993, Collingridge et al., 2010, Martin et al., 2000). Our results from the previous and present studies provide strong evidence that MSD not only impairs hippocampal LTP, but also facilitates the expression of LTD in the offspring (Peng et al., 2016) (Fig. 1). Thus, the alterations of hippocampal LTP and LTD in the offspring of MSD may contribute to the deficits of cognitive and emotional functions. A growing body of studies have confirmed the involvement of regulated AMPAR endocytosis in the expression of LTD and LTP decay (Ahmadian et al., 2004, Dong et al., 2015, Luscher et al., 1999, Man et al., 2000, Rumpel et al., 2005). Blocking AMPAR endocytosis with the GluA23Y peptide is able to prevent hippocampal LTD and LTP decay, and consequently promotes short-term memory into long-term memory (Dong et al., 2012, Dong et al., 2015). In the present study, we demonstrate that MSD-induced LTP impairment and LTD expression are both results of increased GluA2-containing AMPAR endocytosis (Fig. 2). More importantly, systemic administration of GluA23Y peptide is not only able to prevent MSD-induced alterations in hippocampal synaptic plasticity, including both facilitated LTD and impaired LTP (Fig. 1), but also MSD-induced impairments of cognitive and emotional functions in the offspring of MSD (Fig. 3, Fig. 4, Fig. 5). Our work therefore provides the evidence for a critical role of GluA2-dependent endocytosis in MSD-induced memory deficit in the offspring. It is interesting to note that the decreased synaptic GluA2 subunit observed after MSD was not associated with any notable changes in other AMPAR subunits, including the GluA1 and GluA3 subunits. One possible explanation might be the removal of GluA1/GluA2, followed by the insertion of half the number of GluA1 homomeric AMPARs, to balance out the GluA1 level at the synapse. In addition, we have only tested the short-term effects of inhibiting AMPAR endocytosis on cognitive and emotional functions in the offspring of MSD in the current study. However, MSD has long-term effect on the offspring even up to a lifetime. Thus, further experiments on examining the long-term influence of AMPAR trafficking on the offspring of MSD need to be carried out in the future study. MSD has been suggested to be associated with increased frequency of neurodevelopmental disorders in offspring in humans. However, due to the poor understanding of its underlying cellular and molecular mechanism, there has been no effective treatments for the affected offspring. Results presented in the current study strongly suggest that endocytosis of AMPARs has a critical role in causing impaired LTP and increased LTD, and hence some of the behavioral alterations. The fact that GluA23Y can prevent MSD-induced AMPAR endocytosis, thereby restoring normal synaptic plasticity and reducing behavioral impairments in the offspring provides a scientific basis for the development of AMPAR endocytosis blockers, such as GluA23Y, as potential therapeutics for treating the learning and memory deficits associated with offspring of MSD. In this regard, it is particularly relevant to note that clinical evaluations of Tat-based peptide therapeutics, similar to the Tat-GluA23Y described here, has been proven not only safe but also therapeutically effective to treat brain disorder in human following an intravenous application (Hill et al., 2012). Thus, the Tat-GluA23Y described here or its derivatives may have the therapeutic potential as effective treatment for behavioral alterations in the offspring of MSD.