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The Journal of Neuroscience, March 3, 2004, 24(9):2133-2142; doi:10.1523/JNEUROSCI.1554-03.2004

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Development/Plasticity/Repair
Adenovirally Expressed Noggin and Brain-Derived Neurotrophic Factor Cooperate to Induce New Medium Spiny Neurons from Resident Progenitor Cells in the Adult Striatal Ventricular Zone

Eva Chmielnicki,¹ Abdellatif Benraiss,¹ Aris N. Economides,² and Steven A. Goldman^1,3

¹Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, ²Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, and ³Department of Neurology, University of Rochester, Rochester, New York 14642

Neurogenesis from endogenous progenitor cells in the adult forebrain ventricular wall may be induced by the local viral overexpression of cognate neuronal differentiation agents, in particular BDNF. Here, we show that the overexpression of noggin, by acting to inhibit glial differentiation by subependymal progenitor cells, can potentiate adenoviral BDNF-mediated recruitment of new neurons to the adult rat neostriatum. The new neurons survive at least 2 months after their genesis in the subependymal zone and are recruited primarily as GABAergic DARPP-32⁺ medium spiny neurons in the caudate-putamen. The new medium spiny neurons successfully project to the globus pallidus, their usual developmental target, extending processes over several millimeters of the normal adult striatum. Thus, concurrent suppression of subependymal glial differentiation and promotion of neuronal differentiation can mobilize endogenous subependymal progenitor cells to achieve substantial neuronal addition to otherwise non-neurogenic regions of the adult brain.

Key words: Huntington's disease; neurogenesis; subependymal zone; stem cells; gene therapy; regeneration

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Received June 13, 2003; revised January 7, 2004; accepted January 9, 2004.

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