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) functions as a major output nucleus of the basal ganglia, exerting tonic inhibitory control over thalamic and midbrain targets. Although lipid metabolic disturbances have been implicated in neuropsychiatric disorders, how such disturbances affect SNr circuitry and dopaminergic regulation remains poorly understood. Here, we identify a critical role for the lipid transport protein PDZD8 in maintaining basal ganglia circuit integrity. PDZD8 deficiency induces pronounced lipid and lipofuscin accumulation selectively within the SNr. This accumulation is accompanied by enhanced inhibitory inputs from the striatum and reduced SNr projections to the thalamus and midbrain dopaminergic nuclei, indicating a reorganization of inhibitory output pathways. As a consequence, dopaminergic neurons exhibit functional disinhibition and hyperactivation, which in turn reinforces striatal inhibitory signaling, forming a maladaptive feedback loop within the basal ganglia-thalamocortical circuit. Notably, our previous studies demonstrated that PDZD8-/- mice exhibit hyperactivity, reduced anxiety, impaired fear memory, and increased sensorimotor gating--behavioral features relevant to neurodevelopmental disorders. Together, these findings suggest that lipid accumulation-driven disruption of SNr inhibitory output and dopaminergic regulation may underlie behavioral abnormalities associated with PDZD8 deficiency. Our study highlights PDZD8 as a key regulator of metabolic-circuit coupling in the basal ganglia.