Dissecting the contribution of serotonergic circuit dysfunction to behavioural and synaptic abnormalities in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare genetic condition caused by mutations that overactivate a key growth pathway in the cell. People living with TSC often suffer from epilepsy and benign tumours, but also from serious neuropsychiatric problems, such as social difficulties, anxiety, impulsivity, and aggressive behaviour, collectively known as TAND (TSC-associated neuropsychiatric disorders). While treatments for seizures and tumours exist, there are currently no effective therapies for these behavioural and cognitive symptoms, which greatly impact quality of life. This project focuses on the brain’s serotonin system, which plays a central role in regulating emotions and social behaviour. Although serotonin is known to influence anxiety and mood, its involvement in TSC has never been studied in detail. We will use an established mouse model of TSC to track how serotonin nerve fibres develop after birth in brain regions that control social and emotional behaviour. We will also test whether stimulating serotonin activity during early life can restore normal brain connectivity and behaviour in these mice. Understanding how serotonin dysfunction affects the developing brain in TSC will help explain why patients show such complex behavioural symptoms. In the long term, these results could open new paths toward treatments that target the serotonin system, potentially repurposing existing antidepressant drugs, to improve the lives of people affected by TSC and related neurodevelopmental disorders.