Differences in Neuronal Numbers, Morphology, and Developmental Apoptosis in Mice Nigra Provide Experimental Evidence of Ontogenic Origin of Vulnerability to Parkinson’s Disease

Abstract

Parkinson disease (PD) prevalence varies by ethnicity. In an earlier study, we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6 J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study, we investigated if the differences have a developmental origin. Substantia nigra was evaluated at postnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6 J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains until P14. A drastic decline thereafter was specific to C57BL/6 J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6 J. Accordingly, in comparison to C57BL/6 J, the nigra of CD-1 and reciprocal crossbreds possessed cytomorphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds was seen at P2 and P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF, and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appears to be better features that reflect as MPTP resistance at adulthood. Thus, variable MPTP vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.

Fibrinogen and Complement Factor H Are Promising CSF Protein Biomarkers for Parkinson’s Disease with Cognitive Impairment─A Proteomics–ELISA-Based Study

“…This test was performed with the following slight modifications of our previously described protocol. ,,, C57BL/6J mice have been extensively used in our lab because they are susceptible to MPTP (mimicking PD), − so for this particular experiment also, we selected the same strain of mice. The mice were placed on the top of a vertical wooden rough-surfaced pole (diameter 1 cm, height 55 cm; one mouse at a time).…”

Fibrinogen and complement factor H: The two crucial markers of Parkinson’s disease with cognitive impairment

“…and the experiments were conducted according to the CPCSEA and NIH guidelines. Briefly, 15-17 weeks old C57BL/ 6J mice (Vidyadhara et al, 2019(Vidyadhara et al, , 2021 were maintained in the Central Animal Research facility (CARF), NIMHANS. We used both female and male mice weighing approximately 20g and 25 g respectively.…”