We study primarily animal models of DA terminal replacement including 1) grafting new dopamine neurons, and 2) trophic factor induced sprouting of remaining DA neurons. Both approaches have been used with intermittent success in clinical trials for PD, and are aimed at restoring lost DA innervation in the target brain region to which nigral DA neurons project; i.e.. the striatum. We also study the relationship of striatal pathology to the development of levodopa-induced dyskinesias in rodent models of PD.
The goal of our research is to understand why experimental therapies aimed at replacing DA terminals in the PD brain have given largely disappointing results in clinical trials in individuals with PD, and how we can more consistently and effectively remodel the circuitry of the parkinsonian brain to improve therapeutic outcome of such therapies and prevent dyskinetic side-effects of standard pharmacotherapy
Sample Laboratory Projects
Studies in our lab (Soderstrom K, et al., Neurobiol Dis 2008) have demonstrated that synaptic remodeling is a key feature of graft--induced dyskinesias in a rat model of PD following engraftment of new DA neurons. While these studies indicate a direct link between synaptic structural changes and dyskinesia behavior, there remains a lack of information on why such changes in synapse architecture occur in the parkinsonian brain, and whether these changes can be prevented or reversed.
In advanced PD and in rodent models of severe DA depletion there is marked atrophy of dendrites and dendritic spines on the principal neuron found in the striatum, specifically the medium spiny neuron (MSN). Since MSNs are the primary targets of inputs from nigral dopamine neurons it is possible that the structural abnormalities of MSNs in the DA-depleted striatum could result in inappropriate graft–host contacts leading to abnormal behaviors (e.g. dyskinesias) and/or suboptimal behavioral recovery. We recently demonstrated that even with grafting suboptimal numbers of cells, a specific intervention that is capable of maintaining normal spine density on the MSNs results in overall superior behavioral efficacy derived from the newly grafted DA neurons (Soderstrom K, et al., Eur J Neurosci. 2010). However, many issues remain to be established prior to translating this finding into improving treatment for PD.
As a critical step toward the goal of understanding the biology of dyskinesias in PD patients, we are building upon the combined expertise of our laboratory and that of collaborator Dr. Krystof Bankiewicz at University of California San Francisco, to examine the role of synapse remodeling in dyskinetic parkinsonian non-human primates (NHPs), the model most relevant to PD patients. The Steece-Collier laboratory is involved with post-mortem analyses and examination of structural remodeling following DA terminal replacement in this important preclinical model.
Steece-Collier Laboratory Personnel
Pictured Left to Right: Kibrom Gebre-Egziabher, Kellie Sisson, Nathan Levine, Kathy Steece-Collier, Katherine Reterstorf, Jennifer Stancati.
Jennifer Stancati, B.F.A.
Jennifer Stancati has worked in the Steece-Collier laboratory since 2002. She received a BFA from the International School of Design and Technology in Chicago and has been in science since 2002. Her areas of expertise include computer-assisted microscopy, ultramicrotomy, immunohistochemistry, and electron microscopy tissue processing. Her hobbies include crocheting and she’s considering extreme couponing.