Transplantation site influences the phenotypic differentiation of dopamine neurons in ventral mesencephalic grafts in Parkinsonian rats
2017
Foetal midbrain progenitors have been shown to survive, give rise to different classes of
dopamine neurons and integrate into the host brain alleviating Parkinsonian symptoms
following transplantation in patients and animal models of the disease. Dopamine neuron
subpopulations in the midbrain, namely A9 and A10, can be identified anatomically based on
cell morphology and ascending axonal projections. G protein-gated inwardly rectifying
potassium channel Girk2 and the calcium binding protein Calbindin are the two best available
histochemical markers currently used to label (with some overlap) A9- and A10-like
dopamine neuron subtypes, respectively, in tyrosine hydroxylase expressing neurons both in
the midbrain and grafts. Both classes of dopamine neurons survive in grafts in the striatum
and extend axonal projections to their normal dorsal and ventral striatal targets depending on
phenotype. Nevertheless, grafts transplanted into the dorsal striatum, which is an A9 input
nucleus, are enriched for dopamine neurons that express Girk2. It remains to be elucidated
whether different transplantation sites favour the differential survival and/or development of
concordant dopamine neuron subtypes within the grafts. Here we used rat foetal midbrain
progenitors at two developmental stages corresponding to a peak in either A9 or A10
neurogenesis and examined their commitment to respective dopaminergic phenotypes by
grafting cells into different forebrain regions that contain targets of either nigral A9 dopamine
innervation (dorsal striatum), ventral tegmental area A10 dopamine innervation (nucleus
accumbens and prefrontal cortex), or only sparse dopamine but rich noradrenaline innervation
(hippocampus). We demonstrate that young (embryonic day, E12), but not older (E14),mesencephalic tissue and the transplant environment influence survival and functional
integration of specific subtypes of dopamine neurons into the host brain. We also show that
irrespective of donor age A9-like, Girk2-expressing neurons are more responsive to
environmental cues in adopting a dopaminergic phenotype during differentiation postgrafting.
These novel findings suggest that dopamine progenitors use targets of A9/A10
innervation in the transplantation site to complete maturation and the efficacy of foetal cell
replacement therapy in patients may be improved by deriving midbrain tissue at earlier
developmental stages than in current practice.
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