Investigating links between regulatory T-cell depletion and psychosis
Lead Research Organisation:
Cardiff University
Department Name: School of Medicine
Abstract
Psychotic-mood spectrum disorders significantly affect an individual's quality of life and place a large burden upon society.
Genetic risk variants for such disorders converge upon neuronal, histone and immune pathways [1]. One of the most consistent immune findings across psychotic-mood spectrum disorders is a reduction in the proportion of circulating regulatory T-cells [2-4] which may be reversed with medication [5]. We have argued that the effects of Treg depletion on brain myelination processes may confer postpartum psychosis risk in women [6].
We aim to systematically investigate, for the first time, the consequences of acute Treg depletion, with a view to understanding how reduced Treg levels might influence relevant affective (fear/anxiety), cognitive (sensory processing and attention) and immune phenotypes; we will then attempt to rescue any abnormalities identified with immunomodulatory or antipsychotic drugs.
We will use two mouse models in which Treg complement can either be partially (anti-CD25 antibody administration) or fully (diphtheria-toxin (DT) administration to transgenic mice expressing DT receptor on Tregs) depleted, to recapitulate the clinical situation, or to elicit maximal phenotypic effects, respectively. The acute experimental manipulations have no effect on gross health/wellbeing. In a recent pilot study, we have shown that acute, complete Treg depletion in adult female mice is associated with significantly altered brain expression of several genes implicated in psychosis e.g. Gbp4, Lcn2, Sgk1 and Ifitm3. With co-applicants from Bristol with expertise in genetic epidemiology, we will test whether genes/pathways sensitive to Treg depletion are enriched for genetic risk variants associated with psychotic mood disorder, linking our animal work to human genetic risk variants.
The mouse experimental manipulations will be performed in male and female wildtype animals, at key developmental timepoints, and, in females, in the postpartum period. The Behavioural Genetics Group have considerable experience in developing and running sophisticated behavioural/cognitive assays, and via the Neuroscience and Mental Health Research Institute, we have access to expertise in numerous aspects of neuroscience.
Genetic risk variants for such disorders converge upon neuronal, histone and immune pathways [1]. One of the most consistent immune findings across psychotic-mood spectrum disorders is a reduction in the proportion of circulating regulatory T-cells [2-4] which may be reversed with medication [5]. We have argued that the effects of Treg depletion on brain myelination processes may confer postpartum psychosis risk in women [6].
We aim to systematically investigate, for the first time, the consequences of acute Treg depletion, with a view to understanding how reduced Treg levels might influence relevant affective (fear/anxiety), cognitive (sensory processing and attention) and immune phenotypes; we will then attempt to rescue any abnormalities identified with immunomodulatory or antipsychotic drugs.
We will use two mouse models in which Treg complement can either be partially (anti-CD25 antibody administration) or fully (diphtheria-toxin (DT) administration to transgenic mice expressing DT receptor on Tregs) depleted, to recapitulate the clinical situation, or to elicit maximal phenotypic effects, respectively. The acute experimental manipulations have no effect on gross health/wellbeing. In a recent pilot study, we have shown that acute, complete Treg depletion in adult female mice is associated with significantly altered brain expression of several genes implicated in psychosis e.g. Gbp4, Lcn2, Sgk1 and Ifitm3. With co-applicants from Bristol with expertise in genetic epidemiology, we will test whether genes/pathways sensitive to Treg depletion are enriched for genetic risk variants associated with psychotic mood disorder, linking our animal work to human genetic risk variants.
The mouse experimental manipulations will be performed in male and female wildtype animals, at key developmental timepoints, and, in females, in the postpartum period. The Behavioural Genetics Group have considerable experience in developing and running sophisticated behavioural/cognitive assays, and via the Neuroscience and Mental Health Research Institute, we have access to expertise in numerous aspects of neuroscience.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013794/1 | 01/10/2016 | 30/09/2025 | |||
| 2439736 | Studentship | MR/N013794/1 | 01/10/2020 | 31/03/2024 | Eleanor Bird |