Dendritic Remodeling and Parkinson's Disease

The proximate cause of Parkinson's disease (PD) is the loss of striatal dopamine (DA). This results in a variety of compensatory responses in surviving DA neurons. While these changes typically increase DA release and tone in the face of a decrease in the DA innervation, changes in the postsynaptic neurons that receive DA inputs may be deleterious. In particular, striatal DA loss is accompanied by a decrease in the density of dendritic spines on the medium spiny neurons (MSNs). The changes in dendritic spines, upon which the DA receptors are found, may be responsible for the loss of response to DA replacement treatment late in the course of PD.

Glutamatergic transmission regulates dendritic spine density. DA axons terminate onto the neck of MSN dendritic spines, with glutamatergic corticostriatal axons forming synapses onto the spine head. This synaptic architecture between DA and glutamate (Glu) axons and dendritic spines suggests that the loss of DA may lead to decreased gating of Glu inputs to the spine, culminating in retraction and loss of certain dendritic spines.

We are exploring the mechanisms of dendritic spine remodeling in a programmatic effort involving Drs. Roger Colbran, Danny Winder, Tom Montine (Univ. Washington), and Diana Neely. We have found that the loss of signaling through the D2 receptor is responsible for the dendritic changes, which include both changes in spine density and morphology. We speculate that DA denervation of MSNs leads to a glutamate-mediated increase in [Ca2+]i. The loss of DA also results in marked changes in CaMKIIa, which regulates phosphorylation and membrane insertion/localization of certain glutamate receptor subunits. CaMKII regulation and the role of the key phosphatases, particularly calcineurin, are being explored in detail. These studies will shed new light on the mechanisms subserving striatal changes in PD and may provide new therapeutic strategies for Parkinson’s disease.