Tryptophan-enriched diet improves social behavior in a mouse model of tuberous sclerosis complex

Background: Tryptophan is an essential dietary amino acid and the sole precursor of serotonin (5-HT), a neurotransmitter that plays a key role in cognition, mood regulation, and sensory processing. Because central serotonin synthesis depends on dietary tryptophan availability, nutritional modulation of tryptophan intake has emerged as a potential strategy to influence brain function and behavior. Disruptions in tryptophan metabolism and serotonergic signaling have been implicated in autism spectrum disorder (ASD), particularly in Tuberous Sclerosis Complex (TSC), a neurogenetic condition frequently associated with ASD. In this study, we investigated whether dietary tryptophan supplementation could modulate brain tryptophan metabolism and improve ASD-related behaviors in the Tsc2^+/- mouse model. Methods: For that, behavioral tests were performed together with in vivo magnetic resonance spetrosocopy (¹H-MRS) and ex vivo high-performance liquid chromatography (HPLC). Results: Behavioral analysis revealed sex-specific improvements following supplementation, including enhanced sociability in females, restoration of social novelty preference in males, and reduced anxiety-like behavior accompanied by increased exploratory activity across groups. These behavioral changes were associated with increased cortical tryptophan levels, as determined by high-performance liquid chromatography. However, no significant alterations in cortical excitation/inhibition balance were detected using in vivo proton magnetic resonance spectroscopy. Conclusions: Together, these findings demonstrate that dietary tryptophan supplementation enhances cortical tryptophan availability and ameliorates ASD-like behavioral phenotypes in Tsc2^+/- mice. Our results highlight the potential of nutritional modulation of tryptophan intake as a non-invasive strategy to influence serotonergic pathways and behavioral outcomes, supporting the development of precision nutrition approaches for neurodevelopmental disorders.