Investigating links between regulatory T-cell depletion and psychosis

Psychotic-mood spectrum disorders significantly affect quality of life and place a large societal burden.

Genetic risk variants converge on neuronal, histone, and immune pathways. A consistent immune finding is reduced circulating regulatory T-cells, which may be reversed with medication. We propose Treg depletion affects brain myelination, possibly increasing postpartum psychosis risk in women.

We aim to investigate acute Treg depletion's consequences to understand how reduced Treg levels influence affective, cognitive, and immune phenotypes, attempting to rescue abnormalities with immunomodulatory or antipsychotic drugs.

We will use two mouse models to partially or fully deplete Tregs, mimicking the clinical situation or eliciting maximal effects. Acute manipulations have no impact on gross health. A recent pilot study showed complete Treg depletion in adult female mice alters brain expression of genes linked to psychosis. With Bristol collaborators in genetic epidemiology, we will test whether genes sensitive to Treg depletion are enriched for genetic risk variants associated with psychotic mood disorders, linking our animal work to human genetic variants.

Experimental manipulations will be performed on male and female wild-type animals at key developmental timepoints and, in females, during the postpartum period. The Behavioural Genetics Group has considerable experience in behavioral/cognitive assays, and through NMHRI, we have access to neuroscience expertise.