PDZD8 deficiency drives lipid accumulation in SNr and dopaminergic disinhibition

The basal ganglia integrate cortical inputs to regulate motor, cognitive, and emotional behaviors through precisely balanced inhibitory and excitatory circuits. The substantia nigra pars reticulata (SNr) serves as a major output nucleus exerting tonic inhibition over thalamic and midbrain targets. However, how lipid metabolic disturbances affect SNr circuitry and dopaminergic regulation remains unclear. Here, we identify a crucial role for the lipid transport protein PDZD8 in maintaining basal ganglia circuit integrity. PDZD8 deficiency leads to marked lipid and lipofuscin accumulation selectively in the SNr, accompanied by enhanced striatal inhibitory inputs and reduced SNr projections to the ventromedial thalamus (VM) and midbrain dopaminergic nuclei (SNc, VTA). This circuit reorganization results in functional disinhibition and hyperactivation of dopaminergic neurons, producing maladaptive reinforcement of striatal inhibition. Our previous findings revealed that PDZD8 ^⁻/⁻ mice exhibit hyperactivity, reduced anxiety, and impaired fear memory, behavioral phenotypes reminiscent of attention-deficit/hyperactivity disorder (ADHD). These findings demonstrate that lipid accumulation in the SNr disrupts inhibitory output and dopaminergic regulation, forming a maladaptive basal ganglia–thalamocortical loop. Our study provides the first mechanistic link between lipid metabolic dysfunction, dopaminergic disinhibition, and ADHD-like behavioral phenotypes, highlighting PDZD8 as a key regulator of metabolic– circuit coupling in the basal ganglia.