Thesis defense Joanna Widomska (Donders Series 606)

12 June 2023

Promotor: Prof. dr. J.K. Buitelaar
Co-promotors: Dr. J.C. Glennon (University College Dublin, Ireland) and Dr. G.J.V. Poelmans

Molecular mechanisms underlying Tourette’s disorder and obsessive-compulsive disorder: insights from animal and human studies

Through animal model and human studies, this thesis aimed at identifying the molecular mechanisms involved in Tourette’s disorder (TD) and obsessive-compulsive disorder (OCD) and finding novel treatment targets. First, TD-/OCD-like behaviors in the PANDAS mouse model were modulated by estradiol and estradiol-regulated molecules, and were reduced by neonatal stress. In a rat model of abnormal involuntary movements (AIMs) – which resemble the tics in TD – the drug Riluzole counteracted AIMs by reducing the activity of the transcription factor CREB1. Further, the molecular landscape of TD – built based on the human omics data – implicated several pathways and processes in the disease, including cAMP and endocannabinoid signaling, multiple metabolic pathways and synaptic functioning. The landscape also yielded clues towards novel potential treatment targets, i.e., FLT3, NAALAD2, CX3CL1-CX3CR1, OPRM1 and HRH2. Lastly, based on genetic data sets, OCD, OCD-like symptoms in the general population and insulin signaling were found to show partial genetic overlap.