Effect of the P2X7 receptor on cortical neurodevelopment of the autism model from maternal immune activation (MIA)

• Grant number: 24/22717-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2025
• End date: May 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Jean Bezerra Silva
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases, AP.TEM

Abstract

Neurodevelopmental disorders are diseases characterized by disturbances in healthy neural development, such as autism spectrum disorders, attention deficit hyperactivity disorder, schizophrenia, among others. In vivo models of maternal immune activation (MIA) exhibit behavioral features found in humans with autism spectrum disorder (ASD), such as decreased social interest and repetitive behavior. Studies have shown that injection of Poly I:C at E12.5 induces extensive activation of maternal immunity, and commensal organisms of the microbiota come to play a pathogenic role through the recruitment of adaptive immunity. In turn, the maternal immune response, via Th17 lymphocytes and interleukin IL-17A, is responsible for deregulating fetal encephalic proteostasis and compromising excitatory activity in cortical regions. In addition to the classic immunogens, gestational insult with ATP is capable of producing effects similar to those observed with LPS and Poly I:C. Initial studies have shown that both genetic knockout of the P2X7 receptor and inhibition of downstream elements recover behavioral alterations and healthy cortical development, however, no aspect of neural functionality has been evaluated. The aim of this project is to investigate the role of the maternal or fetal P2X7 receptor in the development of the MIA phenotype. Thus, the social interest and repetitive behaviour of the offspring, cortical neuronal functionality and the expression of maturation markers will be evaluated. Preliminary results indicate that the C57Bl6 mouse strain colonized by the bacterium induces Th17 cells, increased gene expression of purinergic signaling elements, including the P2X7 receptor, in mouse trophoblasts after Poly I:C injection.