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  • br STAR Methods br Author


    Author Contributions
    Acknowledgments This study is funded by National Institutes of Health (NIH) Grants NS028901 and DC004450 (to L.O.T.); N.L. Tartar Trust Fellowship (to H.-W.L.); DC014878 to T.S.B. We thank members of the Trussell lab for helpful discussions, Dr. Stephen David for assistance with statistical analysis, and Dr. Craig Jahr and Dr. Brett Carter for comments on the manuscript. We thank Michael Bateschell and Ruby Larisch for help with mouse colony management. Stargazer breeder mice were kindly provided by the Puthussery lab at the Casey Eye Institute.
    Introduction Sleep is a naturally recurring state of mind and body. Quality sleep with sufficient duration and regular schedule is known to be essential for normal BMS265246 functioning. However, due to the development of modern society, sleeping deprivation in women, especially during pregnancy, has become a major public health concern as it not only affects the physiological and mental health of the pregnant women, but also the newborns (Chang et al., 2010, Pien and Schwab, 2004). Indeed, epidemiological studies have demonstrated that poor sleep quality during pregnancy is associated with preterm birth (Strange et al., 2009), longer labors and increased cesarean deliveries (Lee and Gay, 2004), preeclampsia (Ekholm et al., 1992), and postpartum depression (Okun et al., 2009). Furthermore, studies in animal models have revealed that maternal sleep deprivation (MSD) is causally related to a reduction in ultrasonic vocalizations in pups (Gulia et al., 2014), which may indicate a disturbance in cognitive development. Consistent with this point of view, we and others have recently reported that MSD at different stages of pregnancy markedly impairs the emotional and cognitive functions in the offspring rats (Peng et al., 2016, Zhao et al., 2014, Zhao et al., 2015). However, the cellular and molecular mechanisms underlying these behavioral alterations remain unclear. It has been well documented that activity-dependent synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), at the glutamatergic synapses in the CA1 region of hippocampus is cellular mechanism underlying certain types of learning and memory (Bliss and Collingridge, 1993, Collingridge et al., 2010, Martin et al., 2000). Our recent work has shown that MSD at different stages of pregnancy impairs in vivo LTP in the hippocampus of the offspring (Peng et al., 2016). Given that the endocytosis of GluA2-dependent α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) plays critical roles in the maintenance of LTP and the expression of LTD (Ahmadian et al., 2004, Dong et al., 2015, Luscher et al., 1999, Man et al., 2000, Rumpel et al., 2005), we hypothesize that MSD may result in facilitated AMPAR endocytosis, thereby leading to the impaired LTP and increased LTD, and such alterations in synaptic plasticity in turn contribute to the changes in emotional and cognitive functions in the offspring rats. In the present study, we investigated this hypothesis by using a combination of immunoblotting assays, electrophysiological recordings and behavioral assessments.
    Materials and methods
    Discussion In the present study, we have not only confirmed that MSD at late stage of pregnancy impairs LTP, but further revealed the facilitated LTD in the hippocampal CA1 area in the offspring rats. Using a combination of biochemistry and treatment with AMPAR endocytosis inhibitor, we are able to demonstrate that MSD-induced impairment of LTP and facilitation of LTD are both results of facilitated GluA2-dependent endocytosis of AMPARs in the offspring rats. More importantly, our results show that treatment with GluA23Y peptide dramatically inhibits the MSD-induced disruptions of spatial learning and memory, which demonstrates that the MSD-induced behavioral alterations are at least in part mediated through the alteration in synaptic plasticity in the offspring. We have therefore provided strong evidence that MSD increases GluA2-dependent AMPAR endocytosis, that in turns causally contributes to the altered synaptic plasticity and cognitive functions in the offspring.