Impact of phosphodiesterase 10A inhibition on repetitive behaviors and the cortico-striatal signaling pathway in the rat model of autism spectrum disorder induced by valproic acid.

• Grant number: 24/09783-2
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fernando Eduardo Padovan Neto
• Grantee: Fernando Eduardo Padovan Neto
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Felipe Villela Gomes ; João Francisco Cordeiro Pedrazzi ; Kuei Y. Tseng ; Per Petersson ; Rafael Naime Ruggiero
• Associated scholarship(s): 25/12677-2 - Behavioral, Electrophysiological, Pharmacological, and Histological Assessments in the Valproic Acid-Induced Animal Model of Autism Spectrum Disorder., BP.TT

Abstract

The cyclic nucleotides cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate) are second messengers widely distributed in most cell types throughout the brain. These cyclic nucleotides convert neural signals into functional responses, effectively modulating neuronal activity. Given the current lack of specific treatments for autism spectrum disorder (ASD), current findings highlight the potential of PDE enzyme inhibitors as promising pharmacological tools. The enzyme PDE10A is a unique signaling molecule, highly expressed only in a single neuronal population and having a unique role in molecular signaling in the striatum. Given the fundamental role of the striatum in mediating repetitive behaviors associated with ASD, this proposal will explore whether the pharmacological modulation of this structure using a PDE10A inhibitor can represent a promising therapeutic pathway. We will use the animal model of ASD in rats induced by in utero exposure to valproic acid (VPA). To evaluate the effect of PDE10A inhibition in the VPA-induced ASD animal model, we will employ behavioral, electrophysiological and immunohistochemical techniques. We will correlate the manifestation of repetitive behaviors with the responsiveness of MSNs to cortical stimulation during adolescence and adulthood. We will investigate the specific impact of PDE10A enzyme inhibition on repetitive behaviors and its influence on the responsiveness of MSNs to cortical stimulation. This approach highlights the opportunity for personalized interventions in ASD, exploring the specific role of the PDE10A enzyme in the striatum. Thus, this proposal aims to establish that PDE10A inhibition is a valuable pharmacological tool to modulate and potentially correct dysfunctional striatal circuits related to ASD-like repetitive behaviors. (AU)