Project Summary / Abstract Repetitive behaviors are commonly observed in disorders such as Obsessive-Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs). These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, many patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs can reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors in multiple animal models displaying repetitive grooming are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.