PDZD8 deficiency drives lipid accumulation in SNr and dopaminergic disinhibition

Abstract

The basal ganglia-thalamo-cortical loop regulates motor, cognitive, and emotional behaviors and plays central roles in action selection, decision-making, habit formation, and reward learning. The substantia nigra pars reticulata (SNr), a major output nucleus of the basal ganglia, exerts temporally precise control over behavior through tonic inhibitory output mediated by parvalbumin (PV)-positive GABAergic neurons. Accumulating evidence implicates abnormalities in cholesterol metabolism in neurological disorders; however, how cholesterol metabolic dysfunction affects basal ganglia circuit regulation remains largely unknown. In our previous studies, we demonstrated brain-specific cholesteryl ester accumulation and attention-deficit/hyperactivity disorder (ADHD)-like behavioral abnormalities in mice lacking PDZD8. Here, we show that PDZD8 deficiency is associated with selective lipofuscin-like lipid accumulation in SNr-PV neurons, accompanied by reduced SNr projections to thalamic and midbrain dopaminergic targets and increased striatonigral connectivity from caudate-putamen neurons. We propose that lipid accumulation may impair SNr-PV neuron function, potentially leading to relative disinhibition of SNr target regions and disruption of the basal ganglia-thalamo-cortical loop. These circuit abnormalities are likely to disrupt action selection and contribute to ADHD-like behavioral phenotypes. Together, our findings identify SNr-PV neurons as a previously unrecognized site of vulnerability to cholesterol metabolic dysfunction and provide a potential mechanistic link between impaired cholesterol homeostasis, basal ganglia circuit disruption, and ADHD-like behaviors. More broadly, our findings highlight an important role for cholesterol metabolism in maintaining basal ganglia circuitry involved in action selection.