Aberrant Synaptic Plasticity: Impact of Dopamine on Graft Outcome

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Dopamine (DA) neuron grafts provides benefit in some individuals with Parkinson's disease (PD), however, overall efficacy is less than would be predicted from the degree of DA replacement provided in some. Further, an undesirable side-effect known as graft-induced dyskinesias develop in some patients. Many issues thought to underlie lack of graft success in PD are being investigated. Primary among these is low cell survival following grafting into the parkinsonian brain. However, we hypothesize that there are critical factors not yet considered that contribute to the overall lack of graft success. Specifically, the primary site for afferent input of nigral DA are medium spiny neurons (MSNs) within striatum. The numerous dendritic ¿spines¿ found on normal MSNs are critical sites of synaptic integration for nigral DA and cortical glutamate signaling. In advanced PD there is a marked atrophy of dendrites and spines on MSNs (McNeill, 1988; Zaja-Milatovic, 2005; Stephens, 2005). Additional alterations in spine morphology are thought to occur in the parkinsonian brain following long-term levodopa treatment (Sgambato-Faure, 2005; Picconi, 2005). The premise of this project is that these severe morphological alterations following severe DA depletion and/or long-term levodopa will have grave consequences for cell replacement therapies despite the number or type (e.g.: stem, embryonic) of cells grafted. Similar to PD, mice and rats with severe DA depletion also show significant decrease in spine density on MSNs. A new mechanism involving dysregulation of intraspine Cav1.3 Ca2+ channels has been found to account for this spine loss. Indeed, absence of Cav1.3 channels in transgenic mice or administration of the Cav1.3 antagonist nimodipine to parkinsonian rats can prevent spine loss in the presence of severe striatal DA depletion (Day, 2006). Identification of this mechanism allows testing the hypotheses put forth in this project: 1) degenerative changes in spine density of MSN has a detrimental impact on DA graft survival and efficacy; 2) altered spine morphology plays a role in the development of levodopa-induced and/or DA graft-induced dyskinetic behaviors. The proposed studies will employ the well-established rat model of parkinsonism & dyskinesia. Using light and electron microscopic analyses & multiple behavioral profiles, we will compare therapeutic benefit and/or development of abnormal behaviors between DA-depleted rats with normal spine morphology to those with significant spine pathology.