Not only compulsivity: The SAPAP3-KO mouse reconsidered as a comorbid model expressing a spectrum of pathological repetitive behaviors

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Abstract
Symptom comorbidity is present amongst neuropsychiatric disorders with repetitive behaviors, complicating clinical diagnosis and impeding appropriate subsequent treatments. This is of particular importance for Obsessive-Compulsive Disorder, Tourette Syndrome and trichotillomania. Here, we analysed in detail the behaviour of the Sapap3-/- mouse model, the currently predominant mouse model for compulsive-like behaviours. We confirm previously reported aberrantly elevated grooming behaviour, which is essentially composed of a pathologically increased number of short grooming bouts. We furthermore detected other elements of repetitive behaviour in Sapap3-/- mice, which do not form part of the classic cephalo-caudal rodent self-grooming sequence. These elements include the sudden, rapid execution of single, isolated movements such as body twitches or head jerks as well as hindpaw scratching episodes. We provide evidence that it is sufficient to avoid hindpaw scratching-induced effects in order to alleviate skin lesions. In order to characterize the symptomatological nature of the previously unreported repetitive behaviours, we pharmacologically challenged these phenotypes by systemic aripiprazole administration, a first-line treatment for tic-like symptoms in Tourette Syndrome and trichotillomania. A single treatment of aripiprazole significantly reduced the number of short but not long grooming events and sudden head-body twitches. The situation was less clear for hindpaw scratching. These findings suggest that the phenotype of the Sapap3-/- mouse model consists of several pathologically repetitive behaviours of different nature. The observation of the presence of different types of repetitive behaviours in the Sapap3-/- mouse model is in line with the high comorbidity of tic-like and compulsive-like symptoms in human TS, OCD or trichotillomania patients as well as with the hypothesis of a shared neurobiological mechanism behind different types of repetitive behaviours, which are present across different neuropsychiatric disorders.

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