Parallel valence processing alterations associated with compulsive behavior in SAPAP3 knockout mice and human OCD

Background

The main symptoms of obsessive-compulsive disorder (OCD) are anxiety, valence processing abnormality, compulsive and repetitive behavior. OCD could be associated with other neuropsychiatric disorders, such as trichotillomania or autism spectrum disorder (ASD) (Lee et al. 2018). It is never easy to develop rodent models for human neuropsychiatric disorders due to the complexity and species-specificity of those conditions. However, the SAP90/PSD95-associated protein 3 (Sapap3) knockout (KO) mouse line is an accepted model for human OCD, due to its anxiety-like and compulsive grooming behavior (Welch et al. 2007). Sapap3 is a postsynaptic scaffold protein of excitatory synapses, with abundant expression in the striatum and other brain regions of mice, including the neocortex and hippocampus. (Welch et al. 2004). The lack of Sapap3 mRNA evokes cortico-striatal synaptic impairment in KO mice, including increased connectivity from dorsal striatum to frontal cortex, similarly to human patients with OCD (Fitzgerald et al. 2011).

Emotional valence is the intrinsic ’good’ness or ’bad’ness of an emotional stimulus. The goal of this preprint was to establish paradigms for assessing emotional valence (the degree of positive or negative stimuli) processing in both OCD patients and Sapap3 KO mice.

Key findings

Depression Anxiety Stress Scales (DASS) was applied to assess depression, anxiety and stress in study participants (Lovibond & Lovibond 1995). OCD patients participated in emotion identification (the ability to distinguish between happy and fearful) and face recall experiments. The parameters assessed were accuracy – correctly identifying expressions – and reaction time.

Sapap3 KO and WT mice were subjected to a number of different behavioral tasks.

Elevated zero maze was applied to assess anxiety-like behavior. Less time spent in the open quadrants is associated with anxiety, while more time in the open quadrants is considered as anxiolytic-like behavior. Repetitive grooming behavior were monitored in an open field arena by cameras.

Auditory fear conditioning was used to assess freezing behavior to tones, while reward-based conditioning paradigm was used to evaluate instrumental reward learning.

Correlations with Clinical and Demographic Variables of OCD patients

The identification accuracy for fearful versus happy faces was positively correlated with participant age, but not with any clinical measures of OCD. Fearful faces were identified faster by OCD patients, relative to happy expression, which  was positively correlated with anxiety and the depression subscale of DASS.

Anxiety-like and repetitive behavior of Sapap3 KO mice

Similarly to the original study (Welch et al. 2007), Sapap3 KO mice spent less time in the open areas of the elevated zero maze and spent more time with repetitive grooming, compared with WT mice.

Sapap3 KO mice exhibit enhanced fear learning and impaired fear extinction

Sapap3 KO mice froze to the tone significantly more times than WT mice during tones 2-4 of fear conditioning and days 2-5 of fear extinction.

Reward based conditioning

Sapap3 KO mice have a selective learning defect under reward conditions with difficulties both in acquiring positive-reinforced behaviors and in maintaining goal-directed responding for rewards.

Overall, OCD patients and Sapap3 KO mice showed similar abnormalities in emotional valence processing.

Why I liked this preprint

In this preprint, clinical data of OCD patients along with the behavior data of the OCD model Sapap3 KO mice are presented, as a great example for translational research.

Questions for the authors

1. Do human OCD participants harbor mutations in the SAPAP3 gene or any other OCD-associated mutations? Do they have positive family history of OCD?
2. In the Methods section, ASD was not mentioned as an exclusion criterion regarding the OCD patients. Were any of the patients diagnosed with ASD or ASD-related symptoms?
3. Sapap proteins interact with several other postsynaptic scaffold proteins, such as Shanks and Homers, and are the organizers of synaptic signaling in the mouse brain (Welch et al. 2004). Mutations in the Shank genes are strongly associated with ASD, in mice and humans as well (Mohrle et al. 2020). Moreover, Sapap3 KO mice also display some ASD-like symptoms, e.g. altered ultrasonic vocalization (Tesdahl et al. 2017) and a recent preprint revealed novel repetitive behaviors in those KO mice (Lamothe et al. 2021). Is it possible that the behavior of Sapap3 KO mice was misinterpreted in the last 14 years and this KO mouse line is not only an OCD, but an ASD model as well?

References

Fitzgerald K.D., Welsh R.C., Stern E.R., Angstadt M., Hanna G.L., Abelson J.L. & Taylor S.F. (2011) Developmental alterations of frontal-striatal-thalamic connectivity in obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 50, 938-48 e3.

Lamothe H., Schreiweis C., Lavielle O., Mallet L. & Burguière E. (2021) Not only compulsivity: The SAPAP3-KO mouse reconsidered as a comorbid model expressing a spectrum of pathological repetitive behaviors. bioRxiv, 2020.01.22.915215.

Lee S.E., Kim J.A. & Chang S. (2018) nArgBP2-SAPAP-SHANK, the core postsynaptic triad associated with psychiatric disorders. Exp Mol Med 50, 1-9.

Lovibond P.F. & Lovibond S.H. (1995) The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther 33, 335-43.

Mohrle D., Fernandez M., Penagarikano O., Frick A., Allman B. & Schmid S. (2020) What we can learn from a genetic rodent model about autism. Neurosci Biobehav Rev 109, 29-53.

Tesdahl N.S., King D.K., McDaniel L.N. & Pieper A.A. (2017) Altered ultrasonic vocalization in neonatal SAPAP3-deficient mice. Neuroreport 28, 1115-8.

Welch J.M., Lu J., Rodriguiz R.M., Trotta N.C., Peca J., Ding J.D., Feliciano C., Chen M., Adams J.P., Luo J.H., Dudek S.M., Weinberg R.J., Calakos N., Wetsel W.C. & Feng G.P. (2007) Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894-U2.

Welch J.M., Wang D.Q. & Feng G.P. (2004) Differential mRNA expression and protein localization of the SAP90/PSD-95-associated proteins (SAPAPs) in the nervous system of the mouse. Journal of Comparative Neurology 472, 24-39.

 

doi: https://doi.org/10.1242/prelights.30144

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