Distinct early development trajectories in Nf1^± and Tsc2^± mouse models of autism

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviors. Males are three times more likely to be diagnosed with ASD than females, and sex-dependent alterations in behavior and communication have been reported both in clinical and animal research. Animal models are useful for understanding ASD-related manifestations and their associated neurobiological mechanisms. However, even though ASD is diagnosed during childhood, relatively few animal studies have focused on neonatal development.

Here, we performed a detailed analysis of neonatal developmental milestones and maternal separation-induced ultrasonic vocalizations (USVs) in two genetic animal models of ASD, neurofibromatosis type 1 (Nf1^±) and tuberous sclerosis complex 2 (Tsc2^±).

Nf1^± and Tsc2^± mice display strikingly distinct developmental profiles regarding motor, strength, and coordination skills. Nf1^± mouse pups mostly show genotype-related differences, whereas Tsc2^± mouse pups mainly present sexual dimorphisms. Furthermore, we found several differences regarding the number of USVs, frequency modulation, and temporal and spectral profile. Importantly, Nf1^± animals tend to present sex- and genotype-dependent differences earlier than the Tsc2^± mouse pups, suggesting distinct developmental curves between these two animal models.

This study provides a nuanced understanding of how these two ASD models differ in their developmental trajectories. It underscores the importance of studying sex differences and early-life developmental markers, as these could offer crucial insights into ASD's progression and neurobiology. The distinct profiles of these models may help guide more targeted therapeutic strategies in the future.