Neural circuits oscillatory activity during social interaction and novel object recognition task in an animal model for Autism

• Grant number: 22/03345-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2022
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Adriana de Jesus de Souza
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 23/14964-3 - Exploring dopaminergic alterations and sociability in an animal model of autism, BE.EP.DR

Abstract

Autism Spectrum Disorders (ASD) are characterized by impairments in sociability, cognition, and communication, and repetitive or stereotyped behaviors. In preclinical studies, in utero valproic acid (VPA) exposure causes the animals to present changes related to the three core symptoms of ASD, including deficits in social and communication skills and repetitive behaviors. Dysregulation of the GABAergic neurotransmission in the brain, which leads to an abnormal excitatory-inhibitory balance, has long been implicated in ASD. Altered excitatory-inhibitory balance, mainly in the prefrontal cortex and hippocampus, which could result from functional loss of GABAergic interneurons expressing parvalbumin (PV), is associated with changes in behavior and oscillatory activity in ASD. Also, gamma activity patterns (30-50 Hz) in in the prefrontal cortex and hippocampus are altered in ASD, which indicates abnormalities in the excitatory/inhibitory balance. Despite the different reports demonstrating changes in oscillatory activity in patients with ASD and in animal models, studies demonstrating changes in the pattern of oscillatory activity in awake behaving animals during social interaction and cognitive tasks are poorly explored. In addition, alpha 5 subunit-containing GABAa receptors (±5-GABAaR), which are expressed mainly in pyramidal neurons in the hippocampus, are proposed as a potential target to treat psychiatric disorders involving changes in the excitatory-inhibitory balance and, due to its selective expression, without induce the typical side effects of benzodiazepines. This project aimed to evaluate the relationship between exposure to VPA during the prenatal period with changes in the function of PV interneurons and the synchronization of neuronal activity during behaviors correlated with ASD and evaluate whether ±5-GABAaR positive allosteric modulators could attenuate these changes. (AU)