Extracellular vesicle dysfunction contributes to synaptic and cognitive deficits in a mouse model of Angelman syndrome.

Abstract

Angelman syndrome (AS) is a devastating neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A. It is characterized by severe cognitive impairment, motor dysfunction, seizures, and developmental delays. Several mouse models of AS reproduce these debilitating features, including impaired memory function and synaptic plasticity, reduced dendritic spine density, and lysosomal alterations. Emerging research highlights the critical role of extracellular vesicles (EVs) in brain development and function, with growing evidence linking EV dysregulation to various neurological disorders. In this study, we first compared key features of EVs between wild-type (WT) and AS mice. EV secretion from forebrain synaptosomes was impaired in AS mice as compared to WT. Importantly, Ube3a was detected in EVs released from WT forebrain synaptosomes, suggesting a role for Ube3a in neuronal communication. We then identified TRPML1, a lysosomal ion channel, as a regulator of EV release and uptake, unveiling a novel molecular mechanism underlying EV dynamics. Furthermore, treatment with WT neuron-derived EVs significantly improved dendritic and spine morphology of cultured hippocampal neurons prepared from AS mice. Remarkably, systemic administration of WT brain-derived EVs restored hippocampal neuronal morphology and improved learning and memory in AS mice. These findings not only enhance our understanding of AS pathophysiology but also support EVs as a promising strategy for treating this currently incurable disorder.