Embryonic dopamine neuron transplantation has provided symptomatic benefit for some individuals with Parkinson’s disease (PD). However, the efficacy of grafting is variable and less than would be predicted from the degree of dopamine replacement provided in many individuals (Freed et al., 2001; Olanow et al., 2003). While results from recent grafting trials for PD are disappointing, the rationale of replacing Selleck Pexidartinib cells lost in PD remains sound and interest in this approach is regaining popularity. Thus, the question remains why this potentially viable therapeutic approach has not yet fully succeeded.

One factor thought to underlie this lack of success is pathology within the parkinsonian striatum, the region of graft placement. It has been shown in patients with PD and animal models of the disease that dopamine depletion is associated with a host of plastic changes in the striatum (Brown & Gerfen, 2006; Deutch, 2006; Collier et al., 2007; Meurers et al., 2009). One such change involves the primary synaptic target of afferent nigral dopaminergic neurons and descending cortical glutamate neurons, the medium spiny neuron (MSN). Normal MSNs have an abundance of dendritic spines, critical sites for synaptic integration of striatal dopamine and glutamate. In advanced PD there is a marked atrophy of dendrites and spines on these

neurons Erastin solubility dmso (McNeill et al., 1988; Stephens et al., 2005; Zaja-Milatovic et al., 2005). Similar pathology is observed in mice and rats with severe dopamine depletion (Day et al., 2006; Neely et al., 2007). While the impact of this altered morphology on dopamine cell replacement is unclear, it would be anticipated Carbohydrate that an absence of these critical input sites would make it difficult for grafted dopamine neurons to re-establish normal connections needed for therapeutic

benefit. It is also possible that the structural abnormalities of MSNs in the dopamine-depleted striatum could result in inappropriate graft–host contacts leading to abnormal behaviors (e.g. graft-induced dyskinesias; GIDs). While little is known about the etiology of GIDs, we recently reported (Soderstrom et al., 2008) that in a rat model of PD aberrant synaptic features following dopamine cell grafting are associated with the expression of graft-mediated motor dysfunction. These data support the idea that abnormal synaptic reorganization within the grafted striatum contributes to the evolution of aberrant motor behaviors; however, the biological contributor(s) to aberrant graft–host connectivity remains uncertain. The current study was designed to test the hypothesis that preventing MSN dendritic spine loss would allow for more appropriate integration of grafted neurons into the host striatum, thus resulting in increased behavioral efficacy and preventing the development of abnormal motor behaviors.