Sex-specific autistic-like endophenotypes in a rat model of Fragile X Syndrome: role of endocannabinoid neurotransmission

Authors:
Fabrizio Ascone (1), Valeria Buzzelli (1), Alessandro Rava (1), Alessandro Feo (1), Antonia Manduca (1,2), Viviana Trezza (1)

Organisations:
1: Department of Science, Section of Biomedical Sciences and Technologies, University “Roma Tre”, Rome, Italy
2: Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy

Presenting author:
Fabrizio Ascone

Exposition date:
Friday, September 15, 2023

Exposition position:
011/1

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability, caused by a mutation in the FMR1 gene. Individuals with FXS often display symptoms of Autism Spectrum Disorder (ASD), including social and communicative deficits, and repetitive behaviors. Due to the X-linked nature of the condition, FXS is more often associated with males. Furthermore, females with FXS typically have a milder presentation of symptoms compared to males. The increased severity of presentation in males and the lower prevalence in females has led to underrepresentation and often exclusion of females in research. However, females with FXS can still experience significant cognitive, behavioral and physical symptoms.

In this study, we aimed to evaluate the presence of sex-specific ASD-like behaviors in the Fmr1-Δexon 8 rat model of FXS using a battery of behavioral tests to evaluate cognitive performance, social behavior, communication, and repetitive behaviors. Furthermore, since we have recently shown that the endocannabinoid system is involved in the behavioral deficits displayed by Fmr1-Δexon 8 male rats, our second aim was to investigate the role of the endocannabinoid system in the altered phenotype displayed by Fmr1-Δexon 8 female rats.

Our preliminary results indicate that Fmr1-Δexon 8 female rats display deficits in the cognitive, social and communicative domain, similar to Fmr1-Δexon 8 male rats. Interestingly, we observed that Fmr1-Δexon 8 female rats display reduced anxiety-like behaviors and increased repetitive behaviors, while male Fmr1-Δexon 8 rats are spared. These findings indicate that Fmr1-Δexon 8 rat females exhibit several ASD-like symptoms. Ongoing experiments are investigating whether the anandamide hydrolysis inhibitor URB597 is able to correct the behavioral changes displayed by Fmr1-Δexon 8 female rats.

Altogether, these findings highlight sex-specific autistic-like endophenotypes in a rat model of FXS and introduce a new therapeutic target for reversing autistic-like symptoms in both sexes.