Aberrant plasticity and its role in the therapeutics and side effects of fetal tissue grafting in parkinsonian rats

Clinical trials delivering fetal tissue grafts to the dopamine-depleted striatum have failed to elicit signficant behavioral improvements and in some patients have resulted in the development of novel dyskinetic behaviors. The goal of this dissertation was to determine the role of aberrant plasticity in the outcome of fetal tissue grafting and in the occurence of dyskinesias. Specifically, we looked at the roles of medium spiny neuron (MSN) dendritic spine loss and the host immune response to grafting. METHODS: In Experiment I, the Cav1.3 L-type calcium channel blocker, nimodipine, was administered to a subset of unilaterally parkinsonian rats to prevent the loss of MSN dendritic spines associated with severe dopamine depletion. Behavioral recovery and dyskinesias were then observed in rats receiving dopaminergic or sham grafts to the dopamine-depleted striatum with either preserved or diminished MSN dendritic spine density. In Experiment 2, a subset of unilaterally parkinsonian rats received peripheral spleen cell injections on weeks 10 and 18 post-grafting to exacerbate the host immune response. Behavioral recovery and dyskinesia were than observed in dopamine-grafted rats with an exacerbated immune response, a moderate immune response and in sham- grafted rats with little to no immune response. Additionally, an ultrastructural evaluation of synaptic contacts between graft and host cells was conducted. In Experiment 3, a subset of unilaterally parkinsonian rats received 10 weeks of daily injections of cyclosporin A and methylprednisone to suppress the host immune response to grafting. Behavioral recovery and dyskinesia were then observed in rats receiving dopaminergic or sham grafts to the dopamine-dpeleted striatum. RESULTS: In Experiment 1, the preservation of MSN dendritic spines with nimodipine resulted in improved behavioral outcome following grafting and a transient attenuation of graft-induced dyskinesia.;These findings were not the result of improved graft survival as no difference was found in grafted cell number between groups. However, a signficant increase in graft innervation was seen with preserved spine density. In Experiment 2, the exacerbation of the host immune response by peripheral spleen cell injection resulted in a transient worsening of graft-induced dyskinesias. Further ultrastructural analysis of grafted striata found a number of atypical synaptic features associated with an increased immune response. Interestingly, 3 of these correlated significantly with graft-induced dyskinesias. In Experiment 3, dopamine-grafted rats receiving immunosuppression showed improvements in levodopa-induced dyskinesias sooner than their non-suppressed counterparts. While grafted groups failed to develop appreciable graft-induced dyskinesias regardless of their immunosuppression regime, a small portion of rats did show a low level of expression. Importantly graft-induced dyskinesia expression correlated significantly with the host immune response as measured by MHC class II expression. CONCLUSION: MSN dendritic spine loss and the host immune response contribute to the outcome of fetal tissue grafting for Parkinson's disease and the expression of graft-induced dyskinesias. It is likely these aberrant plastic responses represent just 2 of a plethora of contributing factors.