A Subpopulation of Dopaminergic Neurons Coexpresses Serotonin in Ventral Mesencephalic Cultures but not after Intrastriatal Transplantation in a Rat Model of Parkinson's Disease

Abstract

Cell replacement therapy is a promising avenue into the investigation and treatment of Parkinson's disease (PD), and in some cases, significant long-term motor improvements have been demonstrated. The main source of donor tissue is the human fetal ventral mesencephalon (FVM), which consists of a mixed neuronal population, and its heterogeneity likely contributes to the inconsistent outcome observed in clinical trials. Therefore, detailed knowledge about the neuronal subpopulations in the VM seems essential for successful cell transplantation. Interestingly, it has been reported that some tyrosine hydroxylase-positive (TH+) neurons in the VM of adult rats and in cultured midbrain-derived neuroblasts coexpress additional neurotransmitters. Thus, the present study investigated, by means of colocalization analyses, the possible expression of GABA or serotonin in TH+ neurons. For that purpose, both fetal rat and human dissociated, organotypic and neurosphere FVM cultures as well as an animal model of PD were investigated. In dissociated rat FVM cultures, approximately 30% of the TH+ neurons coexpressed serotonin, while no colocalization with GABA was observed. Interestingly, coexpression of TH and serotonin was found to be dependent on the time in culture, the plating density, and the exposure to neurotrophic factors, that is, higher cell densities and treatment with brain-derived neurotrophic factor resulted in a significantly reduced coexpression rate. Notably, even though approximately 30% of the dopaminergic neurons in the donor tissue coexpressed serotonin, no colocalization could be detected in grafts 1 month after intrastriatal transplantation into hemiparkinsonian rats. In conclusion, a significant and susceptible subpopulation of dopaminergic neurons in FVM tissues coexpresses serotonin. This might have potential implications for the future selection and handling of cells prior to transplantation in PD.