Extracellular vesicles improve GABAergic transmission in Huntington’s disease iPSC-derived neurons

Abstract

AbstractExtracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs. In both Huntington’s disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation were reported. Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end-result of the pathophysiological cascade has become an interesting possibility. Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs. After differentiating HD human induced-pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and of GABA receptor-mediated ionotropic signaling. Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses on HD-neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-neurons. Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest and CTR lines with predicted synaptic targets. The EVs-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EVs-miRNAs on synapse regulation.