Conditional Knockout of Striatal Gnal Produces Dystonia-like Motor Phenotypes

Abstract

AbstractLoss-of-function mutations inGNALhave been linked to an adult-onset, isolated dystonia that is largely indistinguishable from idiopathic dystonia.GNALencodes Gαolf, a heterotrimeric G-protein α subunit with a defined molecular function to increase the production of the second messenger cAMP. Gαolfis abundant in the striatum, and is the only stimulatory G-protein in many cell types of the striatum. Due to the defined molecular signaling pathway and expression pattern of Gαolf, the clear genetic link to dystonia makesGNALan exciting target to understand the pathological mechanisms of not only this genetic dystonia, but also the larger idiopathic disease. To better understandGNAL-linked dystonia, we generated a novel genetic mouse model that allows us to conditionally knock outGnalin a site and time-specific manner. In the current study we used genetic or AAV based approaches to express Cre to knockout striatalGnalin our novelGnal fl/flmodel. We then performed motor behavioral testing andex vivowhole-cell patch clamp electrophysiology of striatal spiny projection neurons to interrogate how loss ofGnalleads to dystonia. Mice with conditional striatal knockout ofGnalshow hindlimb clasping, other dystonia-like postures, less motor coordination, slowness, and torticollis as compared to age-matched controls. Furthermore, striatal spiny projection neurons show increased excitability inGnalknockout animals. These exciting data are the first to report uninduced, overt dystonia in a mouse model ofGNAL-linked dystonia, and directly correlate these with changes in spiny projection neuron electrophysiological properties. Our results show that adult loss ofGnalin the striatum leads to the development of dystonia, through homeostatic, paradoxical increases in spiny projection neuron excitability, and suggest that therapeutic strategies aimed at decreasing this hyperexcitable phenotype may provide symptomatic relief for patients with disease.One Sentence Summary:WhenGnalis knocked out in the striatum of mice we observe overt behavioral symptoms and hyperexcitability in striatal spiny projection neurons.