Disruption of prepulse inhibition is associated with compulsive behavior severity and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice

Elizabeth E. Manning,Linda M. Saikali,Susanne E. Ahmari,Anna S. Winner,Abigail Y. Wang

doi:10.1038/s41598-021-88769-5

Elizabeth E. Manning, Linda M. Saikali + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-88769-5

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Abstract

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.

Highlights

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals
prepulse inhibition (PPI) was examined in male Sapap3-KO and wild-type (WT) control mice at ~ 8 months of age, when approximately half of KOs (10/18) showed lesions resulting from compulsive grooming
Visual inspection of the data and an F test to compare variance between the groups demonstrated more variability in KOs compared to WTs (F(17,11) = 3.3, p = 0.0499), prompting us to determine whether this heterogeneity within KOs mapped onto other behavioral measures

Summary

Introduction

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals Neural mechanisms underlying these disturbances are unclear; striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap[3] knockout mice (KOs), a widely used preclinical model system for OCD research. Further supporting the role of elevated dopamine in the manifestation of OCD symptoms, dopamine antagonists can be useful as an adjunct therapy in OCD patients that don’t show clinical improvement following treatment with first-line selective serotonin reuptake inhibitors (SSRIs)[26] Together, these results suggest a potential relationship between alterations in striatal dopamine signalling and disruption of both sensorimotor gating and compulsive behavior in OCD. The goal of this study was to probe the relationship between PPI, striatal dopamine receptor levels, and compulsive behavior in Sapap3-KOs using behavioral testing and ex vivo autoradiography

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