Abstract
The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.
Highlights
When neurons communicate, they release excitatory and inhibitory neurotransmitters to activate or inhibit other neurons that share synapses [1,2,3]
The results suggest that Gamma-aminobutyric acid (GABA) and glutamate promote the release of small EVs (sEVs) by neurons, which was consistent with the nanoparticle tracking analysis (NTA) results
New evidence has demonstrated that the GABAergic system, the counterpart of excitatory to inhibitory (E/I) balance and the major inhibitory neurotransmitter system in the central nervous system, is altered significantly and that this contributes to E/I imbalance and further Alzheimer’s disease (AD)
Summary
They release excitatory and inhibitory neurotransmitters to activate or inhibit other neurons that share synapses [1,2,3]. EVs are heterogeneous cell-derived membranous vesicles that are commonly grouped into three types, small EVs (sEVs) (50–150 nm), large EVs (100–1000 nm) and apoptotic bodies (up to 5 μm) based on their size and mode of biogenesis [8]. These sEVs can breach the blood-brain barrier (BBB), emerge as key mediators of the communication among central nervous system (CNS) cell types [9]. In this study, primary cultured neurons were treated with glutamate/GABA/PBS, and sEVs were isolated. We compared the miRNA composition of sEVs isolated from glutamate/GABA/PBS-treated neurons via miRNA sequencing.
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