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T106

EXOSOMES AND A NOVEL MITOCHONDRIAL MECHANISM OF EPIGENETIC REGULATION OF BRAIN PLASTICITY IN TREATMENT RESISTANT DEPRESSION

Benedetta Bigio — Amarjyot Singh2, Josh Dobbin3, Olivia Barnhill3, Yotam Sagi4, Sean O'Sullivan5, Igor D. Bandeira5, Nick Bassano5, Marin Kautz6, Ashly Cochran7, James Kocsis7, Francis Lee7, James Murrough6, Alan F. Schatzberg5, Carla Nasca1 1New York University School of Medicine, 2Nathan Kline Psychiatric Institute, 3Rockefeller University, 4Nathan Kline Psychiatric Institute, New York University School of Medicine, 5Stanford University School of Medicine, 6Icahn School of Medicine at Mount Sinai, 7Weill Cornell,

2026 ASCP Annual Meeting

Treatment resistant depression (TRD) is a leading cause of disability worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Our group provided the first evidence that boosting mitochondrial metabolism of acetyl-L-carnitine (LAC) leads to a rapid and long-lasting antidepressant response in multiple rodent models by activating epigenetic processes of histone acetylation. Our translational work showed decreased levels of this pivotal mitochondrial metabolite LAC in clinical phenotypes of depression linked to childhood trauma and insulin resistance. Unlike the role of systemic mitochondrial metabolism, molecular mechanisms of brain mitochondrial metabolism and the related epigenetic pathways in TRD remain to be determined. Here, we isolated neuronal exosomes from plasma of healthy control subjects and subjects with TRD in the context of transmagnetic brain stimulation (TMS). Subsequently, we characterized key molecular markers of mitochondrial metabolism and the related pathways. Ongoing analyses showed a link between a key mitochondrial marker assayed in neuronal exosomes and a treatment resistant course of illness (n=93, p < 0.05). These findings were specific to neuronal exosomes as no association was found in total (not neuronally-enriched) exosomes (p=0.7). These phenotypes are also characterized by corresponding changes in the levels of key epigenetic markers important for histone acetylation. Ongoing experiments are aimed at determining the role of this pathway in the responses to TMS. In all, these findings suggest that mitochondrial metabolism has important effects on epigenetic processes in patients with TRD and point to a novel model of mitochondrial-related epigenetic regulation as a mechanistic target for the rapid regulation of plasticity.