Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice

Abstract

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch–clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

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Fig. 1: Excessive grooming across age in Sapap3-KO mice, but no major genotype effect on PV+ cells in the striatum.
Fig. 2: Corticostriatal synaptic deficits in mice at 10–20 weeks of age.
Fig. 3: Input specificity of corticostriatal synaptic deficits in Sapap3-KO mice.
Fig. 4: Decreased AMPAR currents but no NMDAR subunit differences at the M1/M2-to-DLS synapses in Sapap3-KO mice.
Fig. 5: Locomotion phenotypes are evident in Sapap3-KO mice by conventional behavioral analysis and quantification of sub-second behavioral syllables.

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Acknowledgements

The authors would like to thank Agnès Hiver and Sébastien Pellat for excellent laboratory assistance and technical support.

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LDS, LCH, JC, MCC, and VP performed experiments. MMS implemented and performed MoSeq analysis. LDS and CL conceptualized and supervised the study. LDS wrote the paper. All authors contributed to and approved the final paper.

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Correspondence to Linda D. Simmler.

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Hadjas, L.C., Schartner, M.M., Cand, J. et al. Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-0747-3

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