Facilitated AMPAR endocytosis causally contributes to the maternal sleep deprivation-induced impairments of synaptic plasticity and cognition in the offspring rats.

Maternal sleep deprivation (MSD) has been suggested to be associated with increased frequency of neurodevelopmental disorders in offspring in both humans and animal models. However, the underlying cellular and molecular mechanism is still unclear. We have recently reported that MSD at different stages of pregnancy impairs the emotional and cognitive functions, and suppresses hippocampal CA1 long-term potentiation (LTP) in the offspring rats. Here, we report that the MSD induced LTP impairment at the CA1 hippocampus of the offspring rats is associated with increased long-term depression (LTD) and reduced expression of postsynaptic GluA2-containing α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs). Importantly, we found that inhibition of AMPAR endocytosis by a synthetic peptide Tat-GluA23Y (3 µmol/kg, i.p.) not only increased level of AMPARs and reduced LTD, but also restored LTP. Moreover, treatment with Tat-GluA23Y peptide markedly alleviated the MSD-induced impairments of spatial learning and memory; and decreased depressive- and anxiety-like behaviors in the offspring. Together, our findings suggest that the MSD-induced postsynaptic AMPAR endocytosis causally contributes to the impairments of hippocampal synaptic plasticity, thereby disrupting the emotional and cognitive functions in the offspring.

Inhibition of AMPAR endocytosis alleviates pentobarbital-induced spatial memory deficits and synaptic depression.

Our previous study has shown that pentobarbital causes memory deficits and impairs hippocampal synaptic plasticity. The Tat-GluA23Y peptide (GluA23Y) prevents activity-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) endocytosis. It enables early-phase long-term potentiation (LTP) to proceed to late-phase LTP allowing short-term memory to convert to long-term memory. The purpose of this study is to explore the potential effects of GluA23Y on pentobarbital-induced memory deficits through behavioral and electrophysiological paradigms. We found that in vivo intrahippocampal infusion of GluA23Y (100µM, 1µl per hippocampus) 30min prior to pentobarbital administration (8mM, 1µl per hippocampus) significantly rescued the pentobarbital-induced deficit of memory retrieval in rats during the Morris water maze test. Pre-incubation of GluA23Y (10µM) partially rescued bath application of pentobarbital-induced synaptic transmission of the CA3-CA1 pathway in hippocampal slices. More importantly, GluA23Y selectively upregulated the synaptic GluA2 expression that was suppressed by pentobarbital. Together, these results suggest that inhibition of GluA2-containing AMPAR endocytosis by GluA23Y increases the pentobarbital-suppressed basal synaptic transmission by upregulating the synaptic GluA2, and then subsequently alleviates spatial memory deficits. Therefore, inhibition of AMPAR endocytosis may be a potential therapeutic way to treat memory disorders caused by anesthetics.

Low-Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Function and Synaptic Plasticity in APP23/PS45 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease leading to dementia, which is characterized by progressive memory loss and other cognitive dysfunctions. Recent studies have attested that noninvasive repetitive transcranial magnetic stimulation (rTMS) may help improve cognitive function in patients with AD. However, the majority of these studies have focused on the effects of high-frequency rTMS on cognitive function, and little is known about low-frequency rTMS in AD treatment. Furthermore, the potential mechanisms of rTMS on the improvement of learning and memory also remain poorly understood. In the present study, we reported that severe deficits in spatial learning and memory were observed in APP23/PS45 double transgenic mice, a well known mouse model of AD. Furthermore, these behavioral changes were accompanied by the impairment of long-term potentiation (LTP) in the CA1 region of hippocampus, a brain region vital to spatial learning and memory. More importantly, 2-week low-frequency rTMS treatment markedly reversed the impairment of spatial learning and memory as well as hippocampal CA1 LTP. In addition, low-frequency rTMS dramatically reduced amyloid-ß precursor protein (APP) and its C-terminal fragments (CTFs) including C99 and C89, as well as ß-site APP-cleaving enzyme 1 (BACE1) in the hippocampus. These results indicate that low-frequency rTMS noninvasively and effectively ameliorates cognitive and synaptic functions in a mouse model of AD, and the potential mechanisms may be attributed to rTMS-induced reduction in Aß neuropathology.