Tourette syndrome (TS) is a neurological disorder characterized by stereotyped involuntary movements. Although the etiology of TS remains unknown, many studies showed increased activity of midbrain dopaminergic neurons projecting to the basal ganglia and cortical areas that could induce involuntary movements and deficits in behavioral inhibition. Also, pharmacological data showed that drugs limiting dopamine (DA) release suppress tics whereas drugs increasing extracellular DA may promote them. DA cell firing, DA synthesis and DA release are tightly controlled by presynaptic DA D2 autoreceptors. Until recently, pharmacological and genetic approaches had failed to address the in vivo role of autoD2Rs because D2Rs are mostly expressed in postsynaptic neurons. We have overcome this difficulty by generating conditional mutant mice selectively lacking D2Rs in DAergic neurons while retaining normal expression in all postsynaptic cells. Mice lacking autoreceptor control of DA transmission (autoDrd2KO) display elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor and hedonic effects of cocaine. AutoDrd2KO mice also show compulsive-like operant responses when working for food. Thus, autoDrd2KO mice are a novel valuable model where to test the DA hyperfunction hypothesis of TS. The goal of this project is to investigate the hypothesis that reduced autoreceptor control of DA transmission impairs motor function and behavioral inhibition. Locomotor activity, spontaneous and stress-induced stereotyped behavior and behavioral reactions in a go/no-go task will be determined in mice lacking D2 autoreceptors, heterozygous autoDrd2KO mice expressing 50% of autoD2Rs and in a novel mutant mouse model that allows temporal control of autoD2R inactivation. Stereotaxic injections of lentivirus expressing Drd2 in the midbrain of autoDrd2KO mice will be done as a proof of concept that rescuing D2 autoreceptor control of DA transmission reduces movement disorders and restores behavioral inhibition. Marcelo Rubinstein, Ph.D., Maria Avale, Ph.D. Institute for Investigations in Genetic Engineering and Molecular Biology, Buenos Aires, Argentina Award: $100,000 Tourette Association of America Inc. – Research Grant Award 2012-2013