Abstract
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, CaV1.3 contributing to increased intracellular calcium and hence to cell death. CaV1.342A, an alternatively spliced short variant of CaV1.3 has increased calcium influx. We, therefore studied the role of CaV1.342 (full-length channel) and CaV1.342A in mouse SNpc in PD pathogenesis by quantifying mRNA levels of CaV1.342 and CaV1.342A 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 CaV1.342 and CaV1.342A in tyrosine hydroxylase (TH) positive DA neurons. Further, mRNA levels of CaV1.342A were higher in SNpc as compared to the cortex. Upon MPTP treatment, mRNA levels of CaV1.342 and CaV1.342A maintained their levels in SNpc in spite of the loss of ~50% of the DA neurons. This indicates that the expression of CaV1.342 and CaV1.342A is maintained at a robust level during the degenerative process in the parkinsonism model.
Highlights
Parkinson’s Disease (PD) is a debilitating movement disorder characterized by locomotor deficits including resting tremor, bradykinesia, rigidity and postural instability
When comparing relative mRNA levels for CaV1.342A and CaV1.342, we found that CaV1.342A
Combined fluorescent in situ hybridization for CaV1.342A and immunohistochemistry for tyrosine hydroxylase (TH) allowed us to demonstrate that mRNAs encoding the short splice variant were present in substantia nigra pars compacta (SNpc) DA neurons in control mice as indicated by orthogonal reconstruction (Figure 2A)
Summary
Parkinson’s Disease (PD) is a debilitating movement disorder characterized by locomotor deficits including resting tremor, bradykinesia, rigidity and postural instability. Pacemaking in VTA DA neurons appears to depend primarily on HCN/voltage-gated sodium channels (Khaliq and Bean, 2010) and the cytosolic Ca2+ in VTA DA neurons during pacemaking is reported to be significantly less as compared to that in DA neurons in SNpc (Guzman et al, 2018) This has led to the hypothesis that Ca2+-dependent pacemaking along with a poor calcium buffering capacity may cause calcium overload through L-type CaV1.3 channel activation in most vulnerable DA SNpc neurons making them preferentially at risk to degeneration (Surmeier et al, 2010, 2017; Liss and Striessnig, 2019)
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