The proximate cause of Parkinson's Disease (PD) is dopamine loss in the striatum. Striatal medium spiny neurons (MSNs) account for >90% of striatal neurons and are the target of midbrain dopamine neurons, with a synaptic architecture involving a dopamine axon synapsing onto the dendritic spine neck and a single corticostriatal glutamatergic axon synapsing onto the head of the spine. Loss of the dopamine input results in an increase in corticostriatal glutamatergic drive onto the MSNs. In PD and animal models of parkinsonism, striatal dopamine loss causes a progressive decrease in MSN dendritic spines. Because dopamine receptors are normally localized to the spine, and because there appears to be a gradual decrease in responsiveness to dopamine replacement therapy late in the course of PD, it has been suggested that the loss of dendritic spines may contribute to motor impairment in PD. We hypothesize that MSN dendritic spine loss is a result of excessive corticostriatal glutamatergic drive and that manipulations that decrease effective corticostriatal glutamatergic signaling of MSNs will prevent or reverse dopamine depletion-induced spine loss. We will test this hypothesis by determining the effects of cortical lesions on MSN dendritic spine density in the dopamine-denervated rat and by assessing the effects of antagonists at NMDA and AMPA receptors on MSN spine density in the dopamine-denervated striatum. Parkinson's Disease (PD) is the second most common neurodegenerative disorder, and has a major adverse impact on patients, family members and caregivers, and the heath care system. While considerable effort has been devoted to understanding the cause of PD, less attention has been directed to understanding the mechanisms that contribute to poor response to treatment late in the course of PD, and to the underlying mechanisms that lead to progressive impairment in the illness. The studies proposed address one potential mechanism involved in poor symptomatic response late to dopamine replacement treatment late in the course of Parkinson's disease and related parkinsonian syndromes.
| Garcia, Bonnie G; Neely, M Diana; Deutch, Ariel Y (2010) Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss. Cereb Cortex 20:2423-32 |
