The role of the mitochondrial function on synaptic dynamics and neurogenesis in cells exposed to rotenone: relevance for psychiatric disorders

• Grant number: 21/03021-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): October 01, 2021
• Effective date (End): September 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Amanda Siena dos Santos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/02041-1 - The role of lysine(K)-deacetylases on mitochondrial disorders's neuroprotection: perspectives of epigenetic therapy for amyotrophic lateral sclerosis and schizophrenia, AP.JP

Abstract

Neurodevelopment, as well as the stages that comprise it, such as proliferation, differentiation and neuronal migration, synapse formation, myelination and synaptic pruning, are dependent on Adenosine Triphosphate (ATP), intracellular calcium buffering and/or the production of Reactive Oxygen Species (EROS). Therefore, all the essential pathways for the development of the Central Nervous System are dependent on mitochondrial functioning. Today, it is known that changes in any of these steps can result in psychiatric disorders such as Schizophrenia (SCZ) and Spectrum Disorder Autistic (TEA). In accordance with such statements, we demonstrate that the administration of Rotenone (Rot), an inhibitor of Complex I (CI) of the electron transport chain, during the critical period of neurodevelopment in rodents, can lead to behavioral changes during adulthood similar to those presented by animal models of schizophrenia, through alterations levels of synaptic proteins and mitochondrial biogenesis. Thus, the objective of this project is to investigate if Rot is able to alter synaptic dynamics and the process of neurogenesis through modifications in mitochondrial function per se and/or by disruption of the structure and polymerization of microtubules. To fulfill our goals, primary Culture of Neurons (CN) and Culture of Neurospheres (CNF) from rats Wistar (control) will be exposed to Rot. Concomitantly, we will check if the possible mitochondrial dysfunctions and/or synaptic disorders promoted by Rot can be reversed and/or mitigated by using Nicotinamide and MitoQ, compounds capable of altering mitochondrial functioning by modulating the CI and antioxidant mechanism, respectively. Thus, the purpose of our study is not only clarify the role of mitochondrial function in synaptic maintenance, as well as in differentiation, neuronal proliferation and migration. Due to the fact that the role of Nicotinamide and MitoQ in these processes, the acquired data can be of great value for the search of new neuroprotective strategies against disorders associated with neurodevelopment. (AU)