Protection of parvalbumin-containing GABAergic interneurons as a target for treating schizophrenia and depression

• Grant number: 23/10785-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2023
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Gabriel Henrique Caceres da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets, AP.JP

Abstract

Evidence indicates that functional impairments of parvalbumin (PV)-containing GABAergic interneurons underlie symptoms of several psychiatric disorders, including schizophrenia and depression. The functional loss of PV interneurons has been associated with redox dysregulation. Due to their high energy demand to maintain their fast-spiking activity, PV interneurons are thought to be more susceptible to oxidative stress and metabolic damage. Studies from our lab indicated that exposure of adolescent rats to stress resulted in behavioral abnormalities and deficits in PV-positive interneurons in the ventral hippocampus. These changes were associated with increased oxidative stress markers and degradation of perineuronal nets (PNNs), which are formed by extracellular matrix aggregates surrounding PV interneurons. Thus, given that increased oxidative stress results in PV interneuron dysfunction, we aim to assess whether drugs with antioxidant properties, such as N-acetylcysteine, attenuate stress-induced damage of PV interneurons and, consequently, the resulting behavioral and electrophysiological abnormalities associated with PV interneuron dysfunction. Furthermore, increased oxidative stress activates enzymes such as extracellular matrix metalloproteinases (MMPs) that degrade PNNs. Thus, inhibitors of these enzymes, such as doxycycline, could also prevent the impact of stress on PV interneurons. Our findings may indicate possible strategies to prevent the deleterious impact of adolescent stress on the development of psychiatric disorders such as schizophrenia and depression.