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The Journal of Neuroscience, September 23, 2009, 29(38):11973-11981; doi:10.1523/JNEUROSCI.2927-09.2009

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Cellular/Molecular
Glutamate Controls Growth Rate and Branching of Dopaminergic Axons

Yvonne Schmitz,¹ James Luccarelli,¹ Minji Kim,¹ Mi Wang,¹ and David Sulzer^1,2,3

Departments of ¹Neurology and ²Psychiatry, Columbia University School of Medicine, and ³Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032

Correspondence should be addressed to either Dr. Yvonne Schmitz or Dr. David Sulzer, Department of Neurology, Columbia University Medical School, 650 West 168th Street, BB308, New York, NY 10032, E-mail: Email: ys290{at}columbia.edu or Email: ds43{at}columbia.edu

Dopamine-releasing neurons of the substantia nigra pars compacta produce an extraordinarily dense and expansive plexus of innervation in the striatum converging with glutamatergic corticostriatal and thalamostriatal axon terminals at dendritic spines of medium spiny neurons. Here, we investigated whether glutamatergic signaling promotes arborization and growth of dopaminergic axons. In postnatal ventral midbrain cultures, dopaminergic axons rapidly responded to glutamate stimulation with accelerated growth and growth cone splitting when NMDA and AMPA/kainate receptors were activated. In contrast, when AMPA/kainate receptors were selectively activated, axon growth rate was decreased. To address whether this switch in axonal growth response was mediated by distinct calcium signals, we used calcium imaging. Combined NMDA and AMPA/kainate receptor activation elicited calcium signals in axonal growth cones that were mediated by calcium influx through L-type voltage-gated calcium channels and ryanodine receptor-induced calcium release from intracellular stores. AMPA/kainate receptor activation alone elicited calcium signals that were solely attributable to calcium influx through L-type calcium channels. We found that inhibitors of calcium/calmodulin-dependent protein kinases prevented the NMDA receptor-dependent axonal growth acceleration, whereas AMPA/kainate-induced axonal growth decrease was blocked by inhibitors of calcineurin and by increased cAMP levels. Our data suggest that the balance between NMDA and AMPA/kainate receptor activation regulates the axonal arborization pattern of dopamine axons through the activation of competing calcium-dependent signaling pathways. Understanding the mechanisms of dopaminergic axonal arborization is essential to the development of treatments that aim to restore dopaminergic innervation in Parkinson's disease.

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Received June 19, 2009; revised Aug. 7, 2009; accepted Aug. 10, 2009.

Correspondence should be addressed to either Dr. Yvonne Schmitz or Dr. David Sulzer, Department of Neurology, Columbia University Medical School, 650 West 168th Street, BB308, New York, NY 10032, E-mail: Email: ys290{at}columbia.edu or Email: ds43{at}columbia.edu

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