Altered striatal dopamine regulation in Adgrl3 knockout mice

Dopamine signaling is essential for regulating movement, learning, and reward processing, and its dysregulation has been implicated in neuropsychiatric conditions such as ADHD and substance use disorder. ADGRL3, an adhesion G protein-coupled receptor enriched in the brain, has been genetically linked to these disorders, and Adgrl3 knockout in animals alters expression of dopaminergic markers and impacts dopamine-related behaviors. However, how ADGRL3 influences dopamine dynamics remains poorly understood. Here, we characterized striatal dopamine release in Adgrl3 knockout mice using complementary ex vivo and in vivo approaches. Fast-scan cyclic voltammetry in acute brain slices revealed increased electrically evoked dopamine release in both dorsal and ventral striatum of Adgrl3 knockout mice. In contrast, in vivo fiber photometry using the dopamine sensor dLight1.2 showed reduced cue-induced dopamine signals in the ventral striatum during an operant fixed interval task. This reduction was accompanied by longer latencies to lever press and retrieve rewards, consistent with altered cue-guided behavioral responses reminiscent of task-switching difficulties in individuals with ADHD. Amphetamine challenge experiments indicated that phasic release capacity was similar between genotypes, suggesting that dopamine stores are intact in Adgrl3 KO mice. Together, these findings reveal that ADGRL3 regulates striatal dopamine release and motivate mechanistic studies of how its loss may alter the spatial organization of dopaminergic terminals.