Phosphodiesterase 2A inhibition corrects the aberrant behavioral traits observed in genetic and environmental preclinical models of Autism Spectrum Disorder

• Published in: Translational psychiatry 2022-03, Vol.12 (1), p.119-10, Article 119
• Main Authors: Schiavi, Sara, Carbone, Emilia, Melancia, Francesca, di Masi, Alessandra, Jarjat, Marielle, Brau, Fréderic, Cardarelli, Silvia, Giorgi, Mauro, Bardoni, Barbara, Trezza, Viviana
• Format: Article
• Language: English
• Subjects: 631/378; 631/378/1595; 82/51; 82/80; Animals; Autism; Autism Spectrum Disorder - chemically induced; Autism Spectrum Disorder - drug therapy; Autism Spectrum Disorder - genetics; Behavioral Sciences; Biological Psychology; Child development; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome - genetics; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Pregnancy; Prenatal exposure; Psychiatry; Rats; Rodents; Valproic Acid - pharmacology
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-022-01885-2

Pharmacological inhibition of phosphodiesterase 2A (PDE2A), which catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), has recently been proposed as a novel therapeutic tool for Fragile X Syndrome (FXS), the leading monogenic cause of Autism Spectrum Disorder (ASD). Here, we investigated the role of PDE2A in ASD pathogenesis using two rat models that reflect one of either the genetic or environmental factors involved in the human disease: the genetic Fmr1- Δ exon 8 rat model and the environmental rat model based on prenatal exposure to valproic acid (VPA, 500 mg/kg). Prior to behavioral testing, the offspring was treated with the PDE2A inhibitor BAY607550 (0.05 mg/kg at infancy, 0.1 mg/kg at adolescence and adulthood). Socio-communicative symptoms were assessed in both models through the ultrasonic vocalization test at infancy and three-chamber test at adolescence and adulthood, while cognitive impairments were assessed by the novel object recognition test in Fmr1- Δ exon 8 rats (adolescence and adulthood) and by the inhibitory avoidance test in VPA-exposed rats (adulthood). PDE2A enzymatic activity in VPA-exposed infant rats was also assessed. In line with the increased PDE2A enzymatic activity previously observed in the brain of Fmr1 -KO animals, we found an altered upstream regulation of PDE2A activity in the brain of VPA-exposed rats at an early developmental age ( p