title: Glycine transporter-1 inhibition promotes striatal axon sprouting via NMDA receptors in dopamine neurons.
abstract: NMDA receptor activity is involved in shaping synaptic connections throughout development and adulthood. We recently reported that brief activation of NMDA receptors on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching. To test whether this mechanism was relevant to axon regrowth in adult animals, we examined the reinnervation of dorsal striatum following nigral dopamine neuron loss induced by unilateral intrastriatal injections of the toxin 6-hydroxydopamine. We used a pharmacological approach to enhance NMDA receptor-dependent signaling by treatment with an inhibitor of glycine transporter-1 that elevates levels of extracellular glycine, a coagonist required for NMDA receptor activation. All mice displayed sprouting of dopaminergic axons from spared fibers in the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion, but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was approximately twice as dense as in untreated mice. The treated mice also displayed higher levels of striatal dopamine and a complete recovery from lateralization in a test of sensorimotor behavior. We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons. Glycine transport inhibitors promote functionally relevant sprouting of surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson's disease.
authors.affiliation: Departments of Neurology, Psychiatry, and Pharmacology, Columbia University Medical Center, New York, New York 10032, and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schmitz
authors.forename: Candace
authors.initials: C
authors.lastname: Castagna
authors.forename: Ana
authors.initials: A
authors.lastname: Mrejeru
authors.forename: José E
authors.initials: JE
authors.lastname: Lizardi-Ortiz
authors.forename: Zoe
authors.initials: Z
authors.lastname: Klein
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D009048:Motor Skills / Q000502:physiology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016627:Oxidopamine