Work

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

Year: 2024

Type: article

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 ( Ddc KI ) mouse model. We found via tyrosine hydroxylase (TH) immunofluorescence staining that the number of DA fibers in the stratum of 14-day-old Ddc KI mice decreased. In TH-stained cleared whole brains of Ddc KI 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 Ddc KI 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 Ddc KI 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 Ddc KI mice. The CellChat program inferred less cell–cell communication between striatal D1/D2 neurons but increased cell–cell communication involving neural precursors in Ddc KI 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. • Patients with severe forms of congenital neurotransmitter deficiency respond poorly to treatments. • In Ddc KI mice, a model of aromatic l -amino acid decarboxylase deficiency, striatal DA innervation was decreased. • In the whole-brain analysis of Ddc KI mice, the nigrostriatal nerve bundles were dispersed. • Single-nucleus RNA sequencing analysis suggested delayed striatal DA axonogenesis and synapse formation in Ddc KI mice. • We hypothesize that dopamine secreted by the first-arrived axon terminals can attract other DA axons to the striatum.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2024.106707