Nigrostriatal tract defects in mice with aromatic l-amino acid decarboxylase deficiency

Abstract

The development of the nigrostriatal dopaminergic (DA) pathway in the brain involves many transcriptional and chemotactic molecules, and a deficiency of these molecules can cause nigrostriatal tract defects. However, the role of the end product, dopamine, in nigrostriatal pathway development has not been described. In the present study, we analyzed a mouse model of congenital dopamine and serotonin deficiency, namely, the aromatic l-amino acid decarboxylase (AADC) deficiency (DdcKI) mouse model. We found via tyrosine hydroxylase (TH) immunofluorescence staining that the number of DA fibers in the stratum of 14-day-old DdcKI mice decreased. In TH-stained cleared whole brains of DdcKI mice, the numbers of DA neurons in the substantia nigra (SN) and the number of DA nerve bundles leaving the SN were both normal. However, we found that the nigrostriatal bundles in DdcKI mice were dispersed, taking aberrant routes to the striatum and spreading over a wide area. The total volume occupied by the nigrostriatal tract was increased, and the fraction of TH staining in the tract was decreased in DdcKI mice. Single-nucleus RNA sequencing analysis for mice 0, 7, and 14 days of age, revealed delayed axonogenesis and synapse formation in the striatum of DdcKI mice. The CellChat program inferred less cell–cell communication between striatal D1/D2 neurons but increased cell–cell communication involving neural precursors in DdcKI mice. Therefore, a congenital deficiency in dopamine affects nigrostriatal axon extension and striatal innervation. These nigrostriatal tract defects may limit the treatment efficacy for patients with TH or AADC deficiency.