Regulatory Proteins modulating Signalling Pathways in Schizophreniaassociated Mouse Models

Abstract

Schizophrenia (SCZ) is a chronic and disabling psychiatric condition that significantly impairs personal, social, and professional life. Better understanding of its pathogenesis and the effects of pharmacological treatments is essential. This project aimed to investigate the impact of two regulatory proteins, p11 and Nuclear receptor related 1 protein (NURR1), on SCZ.

P11, a member of the S100 EF-hand protein family, interacts with serotonin 5-HT1B and 5-HT4 receptors and metabotropic glutamate receptors, enhancing their signalling. These pathways are crucial for the symptoms observed in SCZ. P11 is further linked to depression, by being downregulated in patients and increased by antidepressants in rodents.

NURR1, a transcription factor in the nuclear receptor superfamily, is vital for the development and maintenance of dopaminergic (DAergic) neurons. DAergic dysfunction is a common factor in psychiatric disorders, including SCZ and bipolar disorder. NURR1's role in DAergic signalling and neuroprotection makes it a potential target for therapeutic interventions. Drug development targeting NURR1 could offer new treatments for disorders involving DAergic dysfunction.

Given the importance of these proteins in psychiatric disorders and their involvement in SCZ-relevant circuits, we studied the effects of their depletion on rodent behaviour, brain structure, protein expression, and functional brain changes, reflecting a SCZ-like phenotype. We used, among other tests, prepulse inhibition of the startle response (PPI), a sensorimotor gating (SMG) model, and social interaction behaviours, which are deficient in SCZ patients. Reversal of deficits in these models in rodents indicates potential antipsychotic treatments. We assessed p11's role in regulating SMG and specific brain areas, observing its impact on structural volume and functional changes in the hippocampus, relevant to SCZ pathophysiology.

For NURR1, we focused on its role in SCZ, particularly in pharmacological treatments and hallucinogenic-like states. We investigated NURR1's importance in the claustrum, a thin neuronal structure linked to conscious perception, by examining its high expression in this region and its relevance to hallucinogenic experiences using behavioural assessments and functional brain imaging.

Utilizing clinically translational methods, including SMG assessment, social interaction, and structural and functional brain imaging, our findings indicate that proteins like p11 and NURR1 are crucial for understanding the pathophysiology of SCZ.

Date of Award	1 May 2025
Original language	English
Awarding Institution	King's College London
Supervisor	Diana Cash (Supervisor), Per Svenningsson (Supervisor) & Bastian Hengerer (Supervisor)