Exosomes from WT Mice Enhances Memory Recall-induced IEG Expression and Rescue Dendritic Spines Deficit in Angelman Syndrome Mice

Abstract

Angelman syndrome (AS) is a rare neurogenetic disorder caused by deletion or mutations in the UBE3A gene, which lead to the deficiency of the UBE3A protein in neurons. UBE3A is crucial for normal neuronal communication, as it regulates the turnover of synaptic proteins and synaptic plasticity. Exosomes, small extracellular vesicles released by various cells, including neurons, play important roles in intercellular communication. Exosomes contain a variety of molecules, including proteins and nucleic acids, and can transfer these components between cells. Emerging evidence indicates that exosomes are critical for normal brain functions, and in recent years many studies have investigated the therapeutic potential of exosomes as vehicles for delivering therapeutic cargoes in various neurological disorders. In this study, we investigated the potential role of exosomes in regulating spine morphology in AS mice. Our results showed that activation of the lysosomal calcium channel TRPML1 stimulated exosome release from synaptosomes prepared from adult WT mice, but not from synaptosomes prepared from adult AS mice. Intriguingly, UBE3A was present in exosomes secreted from WT mice. It has been previously shown that hippocampal neurons of AS mice exhibit fewer dendritic spines, as compared to those from WT mice. Incubation of cultured hippocampal neurons from AS mice with conditioned medium from cultured hippocampal neurons from WT mice rescued the number of dendritic spines. Our data suggest that this effect is most likely due to exosomes in the medium, since purified exosomes from conditioned medium of WT neurons produced a similar rescue effect in cultured neurons from AS mice. Moreover, intravenous injection of exosomes prepared from synaptosomes of adult WT mice seemed to enhance contextual memory recall and associated immediate early gene (IEG) expression, and te number of dendritic spines in CA1 pyramidal neurons in adult AS mice. Whether and to what degree UBE3A present in WT exosomes participates in the rescue of AS neuronal morphology remains to be determined. Together, these results reveal both altered exosomal secretion and composition in AS mice. Treatment of AS neurons or adult AS mice with exosomes rescued dendritic spine deficits in vitro and in vivo. These results open new therapeutical approaches for using exosomes as a potential treatment for this disease.