Aberrant somatic L- and T-type calcium channel function in cNurr1 and LRRK2-G2019S mice

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Abstract In Parkinson’s disease (PD), axons of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) degenerate before their cell bodies. Calcium influx during pacemaker firing is suggested to contribute to neuronal loss, but it is not known if, and at which stage of the disease, dysfunctions of voltage-gated calcium channels (VGCCs) occur in DA neurons somata and axon terminals. We investigated T-type and L-type calcium channels in the somata and axon terminals of SNc-DA neurons of mice with a deletion of the Nurr1 gene in DA neurons from an adult age (cNurr1 mice) and mice bearing the G2019S mutation in the gene coding for LRRK2 (G2019S mice). Adult cNurr1 mice displayed motor and DA deficits (symptomatic stage), while middle-aged G2019S mice did not (prodromal stage). We found that the number and morphology of DA neurons as well as most of their intrinsic membrane properties and pacemaker firing were unaltered in cNurr1 and G2019S mice. However, in G2019S mice, but not cNurr1 mice, the function of somatic L-type VGCCs was increased. In cNurr1 mice, the function of somatic T-type VGCCs was reduced, and somatic dopamine-D2 autoreceptors desensitized more. These changes were reversed by a LRRK2 kinase inhibitor in G2019S mice, and by kaempferol, a flavonoid with antioxidant activity, in both G2019S and cNurr1 mice. The role of L-type and T-type calcium channels in controlling dopamine release from axon terminals in the striatum was unaltered in cNurr1 and G2019S mice. Our findings uncover opposite changes, linked to oxidative stress, in the function of two calcium channels in DA neurons somata, but not axon terminals, in symptomatic and prodromal experimental PD models.

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