The proximate cause of Parkinson's disease (PD) is degeneration of substantia nigra (SN) dopamine neurons and the resultant striatal dopamine insufficiency. However, the pathology in PD is not limited to the loss of SN dopamine neurons. Among other sites showing degenerative changes in PD is the thalamic centromedian-parafasicular complex. Glutamatergic efferents from these thalamic neurons project to the striatum, where they target medium spiny neuron (MSN) dendrites. It has previously been shown that disruption of the striatal dopamine projection results in dystrophic changes in MSNs, including a decrease in dendritic length and spine density. However, the possible regulation of MSN dendritic structures by thalamostriatal neurons has not been explored. Axons from the parafascicular nucleus (PF) synapse onto the dendritic shaft of MSNs. We hypothesize that disruption of the striatal projection from the PF results in dystrophic changes in striatal MSN dendrites. We will assess how thalamic and nigral dopamine lesions affect MSN dendritic morphology both in vivo and in vitro. The primary treatment for PD is dopamine replacement therapy, which targets dopamine receptors that are localized to the spines of MSN dendrites. Alterations in MSN dendrites, on which dopamine receptors are localized, may underlie the loss of responsiveness to dopamine replacement therapy in late-stage PD. Understanding how the thalamus contributes to PD pathology is important for the development of improved treatments for the disorder, particularly late in the course of PD when treatment options are limited.
| Kusnoor, Sheila V; Bubser, Michael; Deutch, Ariel Y (2012) The effects of nigrostriatal dopamine depletion on the thalamic parafascicular nucleus. Brain Res 1446:46-55 |
| Kusnoor, S V; Parris, J; Muly, E C et al. (2010) Extracerebellar role for Cerebellin1: modulation of dendritic spine density and synapses in striatal medium spiny neurons. J Comp Neurol 518:2525-37 |
| Kusnoor, Sheila V; Muly, E Chris; Morgan, James I et al. (2009) Is the loss of thalamostriatal neurons protective in parkinsonism? Parkinsonism Relat Disord 15 Suppl 3:S162-6 |
