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Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, striatal dopamine in mice.

Authors :
Nasello, Cara
Poppi, Lauren A.
Junbing Wu
Kowalski, Tess F.
Thackray, Joshua K.
Wang, Riley
Persaud, Angelina
Mahboob, Mariam
Lin, Sherry
Spaseska, Rodna
Johnson, C. K.
Gordon, Derek
Tissir, Fadel
Heiman, Gary A.
Tischfield, Jay A.
Bocarsly, Miriam
Tischfield, Max A.
Source :
Proceedings of the National Academy of Sciences of the United States of America. 5/7/2024, Vol. 121 Issue 19, p1-12. 53p.
Publication Year :
2024

Abstract

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
121
Issue :
19
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
178011276
Full Text :
https://doi.org/10.1073/pnas.2307156121