Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss.
Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the 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 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 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. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release 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.
Garcia
Bonnie G
BG
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Neely
M Diana
MD
Deutch
Ariel Y
AY
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005452:Fluoresceins; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure*; D009924:Organ Culture Techniques; D009930:Organic Chemicals; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining / Q000379:methods
D018683:Excitatory Amino Acid Agents; D005452:Fluoresceins; D009930:Organic Chemicals; C435731:fluoro jade; D018698:Glutamic Acid; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine