Objective: Establish the developmental basis for varying nigral dopaminergic (DA) correlates in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) susceptible C57BL/6, MPTP resistant CD-1 and their resistant crossbred mice.

Background: Asian-Indians are less vulnerable to Parkinson’s disease (PD) than the Caucasians. Interestingly their admixed population is at much lesser risk. Studying this phenomenon through mice strains with differential MPTP susceptibility revealed variations in nigral DA neuronal number along with other cytomorphological features in assigning resistance/susceptibility.^1,2

Methods: Postnatal day 2 (P2), P6, P10, P14, P18, P22 and adults of C57BL/6, CD-1 and their reciprocal crossbred mice were studied. Tyrosine hydroxylase (TH) immunostained midbrain sections were evaluated for nigral volume and DA neuronal number by planimetry and stereology, respectively. TH expression and the neuronal morphological development was examined, alongside overall nigral development.

Results: Nigral volume and DA numbers were lesser in C57BL/6 compared to CD-1 and the crossbreds at birth and remained so throughout the development. A significant increase in number and nigral volume was observed in all the strains till P14. However, a drastic fall was seen thereafter only in C57BL/6 before stabilising at adulthood. Interestingly, CD-1 and the crossbreds retained their numbers from P14 to stabilize with supernumerary DA neurons at adulthood. Neuronal size significantly increased from P2 to P10 and then attained their adult morphology in CD-1 and the crossbreds, whereas it continued to increase in C57BL/6, only to stabilize at P22. TH expression and nigra attained its adult architecture at P14 in CD-1 and the crossbreds, whereas at P22 in C57BL/6.

Conclusions: We provide the first unbiased stereological estimation of nigral DA number during postnatal development in mice. CD-1 and the crossbreds by birth acquire resilient cytomorphological features; evidenced by higher number of DA neurons at P2. Absence of neuronal loss in these strains after P14 as seen in C57BL/6 indicates lesser developmental cell death. Faster maturity of DA neurons and nigral architecture provide further evidence for superior developmental characteristics, which might render MPTP resistance at adulthood. This demonstrates that variable MPTP susceptibility and heterogeneity in PD pathogenesis may arise early during development.

References: 1. Vidyadhara DJ, Yarreiphang H, Raju TR, Alladi PA. Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration. Molecular Neurobiology 2016 Oct 4. [Epub ahead of print]

2. Vidyadhara DJ, Yarreiphang H, Abhilash PL, Raju TR, Alladi PA. Differential expression of calbindin in nigral dopaminergic neurons in two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Journal of chemical neuroanatomy 2016 Oct;76(Pt B):82-89

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MDS Abstracts - https://www.mdsabstracts.org/abstract/admixing-augments-nigral-dopaminergic-correlates-during-development-to-impart-resistance-to-mptp-toxicity-at-adulthood/