Grant: CIHR Fellowship

Schizophrenia (Sz) is a common and serious mental illness that affects 1% of world population, but its causes are still unknown. Currently, the leading hypotheses link Sz to four neurotransmitters, or chemicals that carry signals in the brain: dopamine, serotonin, glutamate and GABA. The proposed study, however, focuses on the neurotransmitter acetylcholine because it has been reported that administrating high doses of anticholinergic agents, which block acetylcholine induces schizophrenia-like symptoms, including hallucinations, delusions, negative symptoms, and cognitive impairment. Specifically, we focus on the muscarinic cholinergic system, and muscarinic M4 subtype receptors (M4R), one of the key structures of the muscarinic cholinergic system since any change in M4R may be linked to cognitive dysfunction and negative symptoms, which are treatment resistant, in Sz. Postmortem studies have consistently demonstrated reduced muscarinic receptor availability in the cerebral cortex, basal ganglia and thalamus in patients with Sz in comparison to healthy controls (HC). However, M4R alterations in patients with Sz are understudied due to the lack of technique that differentiates between the five muscarinic receptor subtypes in positron emission tomography (PET) studies. We will bridge this gap by using [11C]-MK-6884, a PET ligand that specifically binds to M4R, to compare M4R availability in living subjects between patients with Sz who are free from antipsychotic treatment and matched HCs. Our study will validate the causal association between muscarinic abnormalities and the pathophysiology of Sz, forming the basis for new and more targeted pharmacotherapy for Sz and improving quality of life for Sz patients.