The α6 GABAA Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome.

Roberto Cadeddu,Laura J Mosher,Karen Odeh,Janet L Fisher,Marco Bortolato,Stefanos Loizou,Daniel E Knutson,James M Cook

doi:10.3390/biom11020175

Abstract

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABAA receptors containing α6 subunits (α6 GABAARs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for α6 GABAARs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to α6 GABAAR PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.

Highlights

Tics are semi-voluntary movements or utterances, typically executed in a contextually inappropriate and repetitive fashion
The main results of this study indicate that DK-I-56-1, the selective positive allosteric modulators (PAMs) of α6
GABAA Rs, reduced tic-related responses in two distinct mouse models of Tourette syndrome (TS), representing complementary aspects of tic phenomenology. While these effects were accompanied by ameliorative effects on the prepulse inhibition (PPI) deficits, they were not generalized to other behavior, underscoring the specificity of the effects of DK-I-56-1 to TS-pertinent behavioral manifestations

Summary

Introduction

Tics are semi-voluntary movements or utterances, typically executed in a contextually inappropriate and repetitive fashion. Tics vary greatly in duration and complexity, they are often manifested as clonic, sudden spasms, such as eyeblinks, facial grimaces, head jerking, throat clearing, and shoulder shrugging. The most disabling tic disorder, Tourette syndrome (TS), is a neurodevelopmental illness characterized by multiple motor and at least one phonic tic for longer than one year [1]. TS is characterized by other phenotypic alterations, such as information processing deficits [2]; in particular, TS patients exhibit alterations of prepulse inhibition (PPI) of the startle reflex [3], an operational index of sensorimotor gating. The causes of TS remain partially elusive, ample evidence has shown that this disorder has a strong genetic predisposition [4].

Methods

Results

Conclusion