Animal models of tic disorders: a translational perspective

Abstract

Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders.

Keywords: Animal models; Dopamine; Tic disorders; Tourette syndrome.

Fig. 1

Prepulse inhibition (PPI) of the acoustic startle reflex. (A) Photograph of acoustic startle apparatus (Med Associates, St. Albans, VT). (B) Image of a mouse placed into the testing cage, mounted across a speaker and on a piezoelectric platform for signal transduction. (C and D) Examples of pulse-alone and prepulse-pulse waves during PPI testing.

Fig. 2

Frame-by-frame image of a “tic-like” manifestation in a D1CT-7 mouse model of Tourette syndrome.

Fig. 3

Systemic (A) and intra-accumbal (B) administration of finasteride counters the deficits in the prepulse inhibition of the startle induced by the dopaminergic agonist apomorphine. Readapted from Bortolato et al. (2008a,b) and Devoto et al. (2012). Values are displayed as mean %PPI (average of three different prepulse loudness levels) ± SEM. ***P<0.001 and **P<0.01 compared to animals treated with saline and vehicle. ^###P<0.001, ^##P<0.01 and ^#P<0.05 compared to animals treated with apomorphine and vehicle. Abbrev.: FIN, Finasteride; VEH, Vehicle; APO, Apomorphine; SAL, Saline; HAL, Haloperidol; NAc, Nucleus accumbens.