Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration

Abstract

Previous studies have shown that serotonin neurons play an important role in the induction and maintenance of L-DOPA-induced dyskinesia in animals with lesion of the nigrostriatal dopamine system. Patients with Parkinson's disease that receive transplants of foetal ventral mesencephalic tissue, the graft cell preparation is likely to contain, in addition to dopamine neurons, serotonin neurons that will vary in number depending on the landmarks used for dissection. Here, we have studied the impact of grafted serotonin neurons--alone or mixed with dopamine neurons--on the development of L-DOPA-induced dyskinesia in rats with a partial 6-hydroxydopamine lesion of the host nigrostriatal projection. In these rats, which showed only low-level dyskinesia at the time of transplantation, serotonin grafts induced a worsening in the severity of dyskinesia that developed during continued L-DOPA treatment, while the dopamine-rich graft had the opposite, dampening effect. The detrimental effect seen in animals with serotonin neuron grafts was dramatically increased when the residual dopamine innervation in the striatum was removed by a second 6-hydroxydopamine lesion. Interestingly, rats with grafts that contained a mixture of dopamine and serotonin neurons (in approximately 2:1) showed a marked reduction in L-DOPA-induced dyskinesia over time, and the appearance of severe dyskinesia induced by the removal of the residual dopamine innervation, seen in the animals with transplants of serotonin neurons alone, was blocked. FosB expression in the striatal projection neurons, which is associated with dyskinesias, was also normalized by the dopamine-rich grafts, but not by the serotonin neuron grafts. These data indicate that as long as a sufficient portion, some 10-20%, of the dopamine innervation still remains, the increased host serotonin innervation generated by the grafted serotonin neurons will have limited effect on the development or severity of L-DOPA-induced dyskinesias. At more advanced stages of the disease, when the dopamine innervation of the putamen is reduced below this critical threshold, grafted serotonin neurons are likely to aggravate l-DOPA-induced dyskinesia in those cases where the dopamine re-innervation derived from the grafted neurons is insufficient in magnitude or do not cover the critical dyskinesia-inducing sub-regions of the grafted putamen. We conclude that it is not the absolute number of serotonin neurons in the grafts, but the relative densities of dopamine and serotonin innervations in the grafted striatum that is the critical factor in determining the long-term effect of foetal tissue graft, beneficial or detrimental, on dyskinesia in grafted Parkinson's disease patients.

How to make a midbrain dopaminergic neuron

“…Similarly, human iPSCs sorted with CORIN and expressing the mDA markers FOXA2 and LMX1A survived grafting in 6-OHDA lesioned rats and induced behavioral recovery without tumor formation (Doi et al, 2014). However, sorting protocols that enrich for SNc/A9 cells have yet to be developed, and it is also important to eliminate cell types such as serotonergic cells that might cause side graft-induced dyskinesias (Carlsson et al, 2009(Carlsson et al, , 2007Politis et al, 2010).…”

Functional Neuroimaging in Parkinson's Disease

“…These include the opioid system, which acts as a modulator of dopamine and a cotransmitter within GABAergic neurons (Fox et al 2006;Hallett and Brotchie 2007), the adenosine system (Calon et al 2004), the serotonergic system (Carta et al 2007;Carlsson et al 2009), and the a2 adrenergic system (Fox et al 2001;Rascol et al 2001). Piccini et al (1997) found reduced binding of [ 11 C]diphrenorphine (a nonselective marker of opioid receptors) in the striatum, thalamus, and anterior cingulate of PD patients with LID compared to without.…”

Stem cells in human neurodegenerative disorders — time for clinical translation?

“…Troublesome off-medication dyskinesias have been observed in a group of patients receiving embryonic mesencephalic grafts (8,9,34). Strategies to prevent their occurrence following cell replacement therapy must be developed; minimizing the number of serotonergic neuroblasts in the transplant material, as suggested by animal studies (35), and distributing the DA neuroblasts evenly over the putamen might both be helpful in this regard. Importantly, PD is a multisystem disorder, and symptoms that are caused by pathology in nondopaminergic systems will not be improved by intrastriatal DA grafts (36).…”