Local iron deficiency in the substantia nigra directly contributes to hyperlocomotion phenotypes

Brain iron is precisely regulated, and disrupted brain iron homeostasis is implicated in neuropsychological disease. Mounting evidence connects the iron status of the substantia nigra (SN) with locomotion-related neural symptomatology. Researchers in this field have long speculated that iron deficiency in the SN directly causes the high-locomotion symptoms observed in neuropsychiatric disorders. However, no direct experimental evidence of a causal relationship has been presented. To explore the relationship between iron deficiency in the SN and locomotion-related phenotypes, we stereotaxically injected the well-documented iron chelator, deferiprone (DFP) into the SN of mice to induce regional brain iron deprivation and subsequently performed behavioral tests. Altered expression of iron metabolism-related molecules was detected in the brain regions with interventions, and behavioral changes were observed. Targeted iron chelation effectively decreased the local iron content of the SN. Among the brain regions examined, only DFP injected into the SN resulted in the hyperlocomotion phenotype. Upon SN iron chelation, transferrin receptor (Tfr) expression was found to be upregulated. Conversely, viral vector-mediated SN-Tfr knockdown was sufficient to induce SN iron deficiency and mimic the hyperlocomotion phenotype. All locomotion changes had a significant negative correlation with iron alteration in the SN. Furthermore, SN iron disturbance also contributed to poor sleep efficiency. Thus, SN iron deficiency directly contributed to triggering both hyperlocomotion and sleep disturbances. This study offers a promising research and therapeutic direction for iron-linked neuropsychiatric diseases.