Data_Sheet_1_CaV1.3 L-Type Calcium Channels Increase the Vulnerability of Substantia Nigra Dopaminergic Neurons in MPTP Mouse Model of Parkinson’s Disease.pdf

Mechanisms underlying the selective vulnerability of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) over those in the ventral tegmental area (VTA) to degeneration in Parkinson’s disease (PD) remain poorly understood. DA neurons of SNpc and VTA are autonomous pacemakers but pacemaking in SNpc but not in VTA is accompanied by calcium influx through L-type calcium channel, Ca_V1.3 contributing to increased intracellular calcium and hence to cell death. Ca_V1.3_42A, an alternatively spliced short variant of Ca_V1.3 has increased calcium influx. We, therefore studied the role of Ca_V1.3₄₂ (full-length channel) and Ca_V1.3_42A in mouse SNpc in PD pathogenesis by quantifying mRNA levels of Ca_V1.3₄₂ and Ca_V1.3_42A in SNpc and followed the change in their levels in MPTP induced parkinsonism mouse model. Using in situ hybridization and immunohistochemistry we observed the localization of mRNA of Ca_V1.3₄₂ and Ca_V1.3_42A in tyrosine hydroxylase (TH) positive DA neurons. Further, mRNA levels of Ca_V1.3_42A were higher in SNpc as compared to the cortex. Upon MPTP treatment, mRNA levels of Ca_V1.3₄₂ and Ca_V1.3_42A maintained their levels in SNpc in spite of the loss of ~50% of the DA neurons. This indicates that the expression of Ca_V1.3₄₂ and Ca_V1.3_42A is maintained at a robust level during the degenerative process in the parkinsonism model.