Astragaloside IV enhances memory and regulates hippocampal synaptic plasticity by reducing GABAergic inhibition of BDNF/TrkB signaling pathway in mice through EGR-1

Abstract Background Astragaloside IV (ASIV) is one of the saponins isolated from Astragalus membranaceus, a widely used traditional Chinese medicine and a health product sold all over the world. However, so far, the effect of ASIV on GABAergic synaptic transmission has not been elucidated yet. In the present study, the effect of ASIV on memory and hippocampal synaptic plasticity was investigated in mice and down-regulated early growth response protein 1 (EGR-1) knockout mice. Methods Behavior tests including radial-arm maze test and shuttle-box test, liquid chromatography-tandem mass spectrometry, western blotting analysis, quantitative PCR, electrophysiological recording, and electron microscopy were used in this study. The difference of data was detected by unpaired student t-test or two-factor analysis of variance (ANOVA) or Mann-Whitney U test. Results ASIV was shown to enhance the learning and memory of mice in behavior tests, such as radial-arm maze test and shuttle-box test, as well as the synaptic plasticity in electrophysiological experiments. Moreover, it significantly reduced the concentration of gamma-aminobutyric acid (GABA) and the expression of glutamate decarboxylase 2 (GAD65) in mouse hippocampus, which was accompanied with decreased ratio of inhibitory synapses, and EGR-1, brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). When EGR-1 was knocked out, the promotive effects of ASIV on memory and synaptic plasticity, as well as the inhibitory effects on GAD65, BDNF and TrkB, were abolished. In addition, ASIV was found to down-regulate the pre-existing EGR-1 baseline to better adapt to the learning stimuli. Conclusions Together, these results demonstrated a novel role of ASIV in enhancing memory and modulating hippocampal synaptic plasticity by decreasing GABAergic inhibition through EGR-1 mediated BDNF/TrkB signaling pathway in mice.

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Pharmacological modulation of AMPA receptor surface diffusion restores hippocampal synaptic plasticity and memory in Huntington’s disease

10.1101/297069 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hongyu Zhang ◽

Chunlei Zhang ◽

Jean Vincent ◽

Diana Zala ◽

Caroline Benstaali ◽

...

Keyword(s):

Synaptic Plasticity ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Signaling Pathway ◽

Surface Diffusion ◽

Ampa Receptors ◽

Molecular Basis ◽

Super Resolution ◽

Long Term Potentiation ◽

Hippocampal Synaptic Plasticity

AbstractImpaired hippocampal synaptic plasticity is increasingly considered to play an important role in cognitive impairment in Huntington’s disease (HD). However, the molecular basis of synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that dysregulation of AMPA receptors (AMPARs) surface diffusion represents a molecular basis underlying the aberrant hippocampal synaptic plasticity during HD. AMPARs surface diffusion is increased in various HD neuronal models, which results in the failure of AMPARs surface stabilization after long-term potentiation (LTP) stimuli. This appears to result from a defective brain-derived neurotrophic factor (BDNF) - tyrosine receptor kinase B (TrkB) - Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling pathway that impacts the interaction between the AMPAR auxiliary subunit stargazin and postsynaptic density protein 95 (PSD-95). Notably, the disturbed AMPAR surface diffusion is rescued, via BDNF signaling pathway and by the antidepressant tianeptine. Tianeptine also restores the impaired LTP and hippocampus-dependent memory as well as anxiety/depression-like behavior in different HD mouse models. We thus unveil a mechanistic framework underlying hippocampal synaptic and memory dysfunction and propose a new perspective in HD treatment by targeting AMPAR surface diffusion.

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