The Translocator Protein (TSPO) as a Multimodal Target for Generalised Anxiety Disorder

Generalised Anxiety Disorder (GAD) is a prevalent and debilitating mental health condition. Current pharmacotherapies suffer from delayed onset, side effects, or poor long-term efficacy, highlighting the urgent need for novel, mechanism-based interventions. The Translocator Protein (TSPO) is a promising, yet under-investigated, target for GAD due to its dual role in neurosteroid synthesis and neuroinflammation regulation, two key pathways implicated in GAD pathophysiology. Despite compelling pre-clinical evidence, TSPO’s therapeutic potential remains unproven due to critical knowledge gaps, particularly regarding the impact of the single nucleotide polymorphism (A147T, rs6971), which impairs TSPO function and druggability, affecting up to 50% of the Caucasian population. Our project will deliver the first comprehensive target validation of TSPO for GAD using a novel pharmacological approach. Using ground-breaking ligands developed in our laboratories that bind both wild-type (WT) and A147T TSPO with nanomolar affinity, we will assess steroidogenic and anti-inflammatory functions in clinically-relevant isogenic iPSC-derived glial cells. In parallel, we will evaluate behavioural and molecular outcomes in WT and A147T TSPO mouse models. This integrative strategy will rigorously define the functional relevance of TSPO in anxiety regulation and its tractability as a therapeutic target, paving the way for the development of genetically robust, fast-acting treatments for GAD.