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Title page for ETD etd-03302010-155007

Type of Document Dissertation
Author Garcia, Bonnie Gale
URN etd-03302010-155007
Title Corticostriatal regulation of medium spiny neuron dendritic remodeling in models of parkinsonism
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Eugenia V. Gurevich Committee Chair
Ariel Y. Deutch Committee Member
Danny G. Winder Committee Member
P. Jeffrey Conn Committee Member
Randy Blakely Committee Member
  • metabotropic glutamate receptors
  • Parkinson's disease
  • dendritic spines
  • dopamine depletion
  • motor cortex
  • nigrostriatal
Date of Defense 2010-03-23
Availability unrestricted
Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex that synapse onto the spine head and dopaminergic inputs from the substantia nigra which synapse onto the necks of dendritic spines completes a triadic arrangement. Striatal DA loss, as occurs in Parkinson’s Disease (PD), results in dystrophic changes in MSN dendrites, including a loss of dendritic spines. This loss of spines has been suggested to reflect removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss.

We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion-induced spine loss by placing motor cortex lesions four weeks after, or at the time of,

6-hydroxydopamine lesions of the SN; animals were sacrificed four weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment.

Because decortication results in a loss of corticostriatal axon terminals, it is possible that signaling molecules in addition to glutamate that are contained in these axons may be the culprit in determining spine changes. We therefore treated cultures (14-15 DIV) with MPP+ to disrupt the striatal DA innervation, and then added a metabotropic glutamate receptor agonist, LY379268, to suppress glutamate release in these cultures. Two weeks later cultures were diOlistically labeled and spine density determined. Treatment of the cultures with the mGluR2/3 agonist completely blocked spine loss in dopamine-denervated cultures.

These studies provide the first evidence to show that MSN spine loss associated with Parkinsonism can be reversed, and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson’s Disease.

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