Altered striatal dopamine regulation in ADGRL3 knockout mice

Perry-Hauser, N. A.; Torres-Herraez, A.; Boumhaouad, S.; Makowicz, E. A.; Lowes, D. C.; Jin, M.; Denny, C. A.; Sulzer, D.; Mosharov, E. V.; Kellendonk, C.; Javitch, J. A.

doi:10.1101/2025.07.31.667389

bioRxiv · 10.1101/2025.07.31.667389

Altered striatal dopamine regulation in ADGRL3 knockout mice

Perry-Hauser, N. A.·Torres-Herraez, A.·Boumhaouad, S.·Makowicz, E. A.·Lowes, D. C.·Jin, M.·Denny, C. A.·Sulzer, D.·Mosharov, E. V.·Kellendonk, C.·Javitch, J. A.

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Abstract

Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

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Perry-Hauser, N. A., Torres-Herraez, A., Boumhaouad, S., Makowicz, E. A., Lowes, D. C., Jin, M., Denny, C. A., Sulzer, D., Mosharov, E. V., Kellendonk, C., Javitch, J. A.. 2025-08-01. Altered striatal dopamine regulation in ADGRL3 knockout mice. https://doi.org/10.1101/2025.07.31.667389

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