ABSTRACT Shank3 , a scaffolding protein, is critical for synaptic structure and function, particularly for the formation and maintenance of dendritic spines. Shank3 mutations are strongly implicated in autism spectrum disorder (ASD) and related neuropsychiatric conditions such as Phelan-McDermid Syndrome (PMS) also known as the 22q13.3 deletion syndrome. Previous work has recognized early hyperexcitability in cortical neurons derived from ASD patients with various gene mutations as a potential common endophenotype. In this study, we examined the effects of exosomes extracted from several cell types on the neurophysiological properties of cortical neurons derived from Shank3 (c.3679insG mutation) induced pluripotent stem cells (iPSCs). First, we sought to understand the implications of exosome-based intercellular communication on the neurophysiology of Shank3 mutant and control neurons by switching their respective exosomes. We found that while control neuron-derived exosomes do not change the neurophysiology of Shank3 neurons, the Shank3 neuron-derived exosomes transfer the early hyperexcitability and other ASD-related phenotypes to control neurons. Next, we also explored the therapeutic potential of mesenchymal stem cells (MSC) and iPSC-derived exosomes from healthy donors in the Shank3 cortical neurons. We demonstrate that both MSC and iPSC-derived exosomes rescue the early hyperexcitability and accelerated maturation of Shank3 neurons. Proteomic analysis of exosomes derived from Shank3 mutant and control neurons, as well as from exosomes derived from MSCs and iPSCs, revealed distinct protein cargoes that may cause changes in the neurophysiological properties of the recipient neurons. Our results hence provide novel insights into the pathophysiology of ASD emphasizing the importance of exosomes in intercellular communication and their potential to influence intrinsic and network properties of neurons. Moreover, our findings support the need for further exploration of exosome-based interventions as potential therapeutics for treating neurodevelopmental disorders.

Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associated Shank3 mutation.