Study of molecular and cellular mechanisms of mental disorders: clinical studies and animal models

• Grant number: 23/07874-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2023
• End date: February 29, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Mirian Akemi Furuie Hayashi
• Grantee: Augusto Anesio
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/13112-8 - Study of molecular and cellular mechanisms involved in mental disorders: clinical and animal models analysis, AP.TEM

Abstract

Mental disorders (MDs) are a group of potentially serious and highly prevalent diseases that affect the Central Nervous System (CNS). Studies aiming to investigate biochemical/molecular and/or cellular changes could assist in the accuracy of diagnosis and provide a better understanding of the neurobiology involved in MDs, thereby enabling the potential identification of new targets for the development of innovative drugs that allow for more effective treatment of symptoms, or even their cure and/or possible prevention. Over the past few years, analyses of cultured cells and/or samples from patients or animal models of schizophrenia (SCZ) have demonstrated that oligopeptidases, such as Ndel1, play a crucial role in brain formation and the progression of MDs such as SCZ. The importance of oligopeptidase activity in neuritogenesis and neuronal migration during embryogenesis and brain formation, as well as the significant differences in the activity of these oligopeptidases in SCZ patients compared to healthy controls, as observed in animal models for SCZ, have been primarily demonstrated by our research group in recent years. In the activities related to the grant in question, we propose the importation of an animal model that allows for conditional knockout of the gene encoding Ndel1. By employing this model, we will investigate how the deletion of this gene in the adult brain affects neurogenesis and neuronal arborization in the prefrontal cortex and hippocampus, as well as the expression of schizophrenia-related predictive behaviors. Based on preliminary results from our clinical studies, we will also investigate in an animal model whether depressive-like behaviors correlate with changes in Ndel1 activity in the blood and brain. Additionally, we propose to investigate whether antidepressant treatment and the therapeutic response of these animals correlate with alterations in Ndel1 activity. Furthermore, based on preliminary findings, we will investigate whether treatment with fluoxetine reverses depressive-like behaviors in rats that overexpress the human DISC1 protein. In this context, through collaboration with the Santos Dumont Institute, we will conduct in vivo electrophysiological recordings to verify whether DISC1 overexpression causes an imbalance between excitatory and inhibitory waves in the prefrontal cortex, as observed in patients with mental disorders. (AU)