Vanderbilt Addiction Center

Dendritic Plasticity in Parkinson's Disease

A decrease in striatal dopamine (DA) concentration underlies Parkinson's disease (PD). DA terminals synapse onto striatal medium spiny neurons (MSNs), forming a triad with corticostriatal glutamatergic synapses; the excitatory cortical input is typically onto the head of the dendritic spine and the DA synapse onto the spine neck. DA is thereby critically positioned to gate excitatory glutamatergic inputs to MSNs. A variety of compensatory mechanisms are set into play by decreased striatal DA levels and attempt to maintain normal function in the face of progressive DA loss. Certain changes may afford some benefit but may ultimately be counterproductive. 6-hydroxydopamine (6-OHDA) lesions of the striatal DA innervation result in decreased dendritic spine density and decreased dendritic length in MSNs; a similar picture has been reported in PD. Glutamate has been shown to regulate spine formation and maintenance through NMDA and AMPA receptors, respectively. We hypothesize that striatal DA depletion results in decreased dendritics spine density by increasing glutamatergic transmission, which causes an increase in intracellular calcium levels. The increase in [Ca2+]i results in spine shortening and loss, thus delimiting excitatory drive onto the MSN. However, these dendritic changes may also limit the effectiveness of DA replacement treatment through loss of dendritic spines, on which DA receptors reside. This programmatic effort will test this hypothesis through four projects. The first project will determine if loss of DA tone at the D2 receptor is responsible for the dendritic changes in MSNs, and test the hypothesis that calcium influx through L-type calcium channels is an effector. The second project examines the dopaminergic regulation of CaMKII in the MSN; this dendritically-transcribed Ca2+-dependant enzyme regulates phosphorylation of the GluRl subunit of the AMPA receptor and 2B subunit of the NMDA receptor, and is thus a key to effectiveness of excitatoty glutamatergic transmission. The third project tests the hypothesis that calcineurin (PP2b), a Ca2+- activated phosphatase recruited by dopamine signaling through the D2 receptor, regulates glutamatergic drive onto MSNs and will determine if the decrease in spine density in MSNs is altered by genetic up- or down-regulation of PP2b. The final project will determine changes in dendritic morphology at both the light and electron microscopic level in postmortem material from PD patients and correlate dendritic changes with clinical status; this work will also determine the forms of synaptic reorganization that accompany spine loss. These projects should shed light on the pathophysiology of PD and may lead to development of new strategies aimed at slowing or halting disease progression. \

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