Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming

Abstract

Tic disorders, including Tourette syndrome (TS), are thought to involve pathology of cortico-basal ganglia loops, but their pathology is not well understood. Post-mortem studies have shown a reduced number of several populations of striatal interneurons, including the parvalbumin-expressing fast spiking interneurons (FSIs), in individuals with severe, refractory TS. We tested the causal role of this interneuronal deficit by recapitulating it in an otherwise normal adult mouse using a combination transgenic-viral cell ablation approach. FSIs were reduced bilaterally by ~40%, paralleling the deficit found post-mortem. This did not produce spontaneous stereotypies or tic-like movements, but there was increased stereotypic grooming after acute stress in two validated paradigms. Stereotypy after amphetamine, in contrast, was not elevated. FSI ablation also led to increased anxiety-like behavior in the elevated plus maze, but not to alterations in motor learning on the rotorod or to alterations in prepulse inhibition, a measure of sensorimotor gating. These findings indicate that a striatal FSI deficit can produce stress-triggered repetitive movements and anxiety. These repetitive movements may recapitulate aspects of the pathophysiology of tic disorders.

Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala

“…AAV6 was infused at a volume of 0.5 l over a 10 min period and allowed to diffuse for 5 min after injection. AAVrh10 CAG.EGFP.FLEX.DTRFLAG.WPRE.pA (described in Xu et al, 2016;A46, titerϭ ϳ10 13 gc/ml) was injected bilaterally into mPFC (AP ϩ3.0, ML 0.4, DV Ϫ4.0) at a volume of 0.25 l. AAVrh10-DTR was injected at 0.05 l/min and allowed to diffuse for 10 min. For the BLA¡NAc experiments, AAV6-Cre was injected into NAc (same volume and rates given above) and AAVrh10-DIO-DTR was injected into BLA (0.2 l/side, DV: Ϫ8.7).…”

Modeling tics in rodents: Conceptual challenges and paths forward

“…However, not every repetitive movement is representative of a tic. Repetitive movements, such as elevated grooming (Kalueff et al, 2016), have been described as recapitulating tics (Xu et al, 2015a; Xu et al, 2015b; Xu et al, 2016); but dysregulated grooming has also been argued to recapitulate obsessive-compulsive symptoms (Ahmari et al, 2013; Greer and Capecchi, 2002; Shmelkov et al, 2010; Welch et al, 2007), trichotillomania (Feusner et al, 2009), autistic stereotypies (Peca et al, 2011; Zhou et al, 2016), Rett syndrome (Yasui et al, 2014), psychostimulant-related behavior (Berridge et al, 2005), and other clinical conditions (Kalueff et al, 2016). Given the evolutionary divergence between rodents and humans, it is unlikely that homologs of tics in mice will fully recapitulate all clinical characteristics of tics.…”

“…In our laboratories, we have used a range of methods to quantify repetitive movements, including manual scoring from videos (Castellan Baldan et al, 2014; Pogorelov et al, 2015; Xu et al, 2015a; Xu et al, 2015b; Xu et al, 2016), automated scoring from videos (Rapanelli et al, in press; Xu et al, 2015a), and repetitive beam-breaks in an open field (Rapanelli et al, 2017; Rapanelli et al, in press). Standardization is needed; however, in light of the discussion above, standardized approaches to quantification of behavioral pathology need to be somewhat flexible – the precise topography of tic-relevant movements may not be identical across models and across contexts.…”

“…The causal relationship of interneuron pathology to TS-relevant behaviors has recently been tested in animal models. Targeted depletion of parvalbumin-expressing GABAergic interneurons (Xu et al, 2016) or of cholinergic interneurons (Xu et al, 2015a) in the dorsal striatum does not produce stereotypic movements at rest, but elevated and dysregulated grooming emerges after acute stress. Given the ability of stress to trigger or worsen tics (Conelea and Woods, 2008; Godar and Bortolato, 2016), this provides good support for the causal relevance of the interneuronal pathology to TS.…”

Tourette syndrome research highlights from 2016

“…How this may relate to lower numbers of parvalbumin-containing interneurons in TS 36 is unclear. An interesting contrast based on the parvalbumin data is provided by a model in which fast-spiking interneurons in the dorsal striatum were ablated 37 . These mice developed anxiety and increased frequency of grooming rituals.…”