The lab focuses on early development of brain connectivity in the context of neuropsychiatric diseases such as autism spectrum disorder or anxiety disorder. We seek mechanistic understanding of variable expressivity of neuropsychiatric phenotypes. Patients suffering from various genetic diseases present variable neuropsychiatric symptoms which often do not correlate with mutation burden. We explore molecular and cellular mechanisms that may regulate this variability using high-throuput methodologies.

We demonstrated that commissural thinning results in the aberrant regulation of anxiety in the zebrafish model of Tuberous Sclerosis Complex (TSC) which provided a mechanistic link between brain anatomy and human TSC-associated neuropsychiatric disorders (TANDs). On top of this, we identified two potential drug targets for particular aspects of TSC – namely ethosuximide for seizures and ANA-12 for seizures and anxiety. TSC is a rare genetic disease that manifests with early symptoms including mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) hyperactivation, cortical malformations, childhood epilepsy, and TANDs. It is caused by mutations in genes encoding for TSC1 or TSC2. We found that lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions and observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. With live imaging of the developing brain, we showed that lack of Tsc2 delayed axonal development and caused aberrant tract fasciculation. This corresponded with the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in non-motor seizures seen by multiple behavioural analyses and live imaging of the brain activity. The Tsc2-deficient zebrafish also exhibited increased anxiety-like behaviour in the open field test or sudden light changes test and had elevated cortisol levels. Both seizures and anxiety could be rescued by reducing tyrosine receptor kinase B (TrkB) signaling identifying novel potential drug target. We also found that the lack of light-preference behaviour in the Tsc2-deficient zebrafish (otherwise exhibiting increased anxiety-like behaviours and elevated cortisol levels) is caused by impaired sensory integration in the left dorsal habenula due to hyperactive mTorC1.

The lab further explores how TrkB pathway interacts with hyperactivated mTORC1 pathway and tries to indentify the intermediate components that could serve as drug targets for future therapies for neurophychiatric disorders.