Defining the Role of Mitochondrial Dysfunction in Autism Spectrum Disorder

• Applicant: Liliana Rojas-Charry, Ph.D.
• Subject Area: Biological Psychiatry
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465907573

Autism Spectrum Disorder (ASD) is an incurable psychiatric disorder that affects behavior and communication. The presentation of ASD is highly heterogeneous, and its incidence is increasing. Mutations in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) and fragile X mental retardation 1 (FMR1), proteins involved in synaptic activity, increase the risk of developing ASD. Mitochondria are present in the synapse, performing different tasks not only associated with energy production and the regulation of calcium signaling. Recent research has demonstrated that the synthesis of mitochondrial proteins occurs at the synapse, contributing to sustaining synaptic activity. However, few studies have addressed in detail how mitochondrial impairments impact ASD in different brain regions and specifically in the synapse. Own preliminary data show differences in oxygen consumption in mouse models of ASD with the strongest phenotype in the striatum, an important brain structure involved in motor and action planning, decision-making, motivation and reward. I also found increased concentrations of reactive oxidative species in the striatum of ASD mice, demonstrating an altered redox environment in the ASD brain. In this project, I plan to study mitochondrial dysfunction and redox modifications of synaptic proteins in the striatum of Shank3 KO and Fmr1 KO mice to clarify the role of mitochondrial dysfunction on synaptic activity in ASD mouse models. Mitochondrial shape, respiration, and ATP generation will be evaluated in striatal tissue and primary striatal cultures. Here, I will use physiological models to elucidate whether ASD results in changes in the abundance and redox modifications of synaptic proteins. My studies will provide new insights into the understanding of ASD and open up novel perspectives in developing effective treatments.

• DFG Programme: WBP Position