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The Journal of Neuroscience, June 30, 2004, 24(26):5922-5930; doi:10.1523/JNEUROSCI.5668-03.2004

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Development/Plasticity/Repair
Rescue of Mesencephalic Dopaminergic Neurons in Culture by Low-Level Stimulation of Voltage-Gated Sodium Channels

Bénédicte Salthun-Lassalle,¹ Etienne C. Hirsch,¹ Jakob Wolfart,² Merle Ruberg,¹ and Patrick P. Michel¹

¹Institut National de la Santé et de la Recherche Médicale U289, Experimental Neurology and Therapeutics, Hôspital de la Salpêtrière, 75013 Paris, France, and ²Integrative and Computational Neuroscience Unit, Centre National de la Recherche Scientifique Unité Propre de Recherche 2191, 91198 Gif-Yvette, France

We used a model system in which dopaminergic (DA) neurons from embryonic rat mesencephalon undergo spontaneous and selective degeneration as they develop in culture. Here, we show that DA cell loss can be prevented efficiently by low concentrations of the Na⁺ channel agonist veratridine. The survival promoting effect of veratridine was reproduced by, but independent of, glial cell line-derived neurotrophic factor. Neuroprotection by veratridine was exquisitely specific to DA neurons, short-lived after withdrawal, and abolished by tetrodotoxin, indicating that activation of voltage-gated Na⁺ channels was crucially involved. Calcium measurements showed that veratridine-induced Na⁺ influx was necessary to maintain intracellular Ca²⁺ within a neuroprotective range through the stimulation of low-voltage activated T-type calcium channels, a mechanism that was distinct from that elicited by high K⁺-evoked depolarization. Interestingly, increasing neuronal excitability by treatment with apamin, an inhibitor of Ca²⁺-activated K⁺ channels, or with ouabain, a blocker of the Na⁺/K⁺-ATPase pump, was also neuroprotective by a mechanism involving T-type calcium channel activation. These results support the idea that mesencephalic DA neurons depend primarily on excitatory input for their survival during development.

Key words: channel; dopaminergic; excitability; GDNF; sodium; trophic

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Received Dec 23, 2003; revised March 22, 2004; accepted May 17, 2004.

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