• Bénédicte Salthun-Lassalle, Etienne C Hirsch, Jakob Wolfart, Merle Ruberg, and Patrick P Michel.
• Institut National de la Santé et de la Recherche Médicale U289, Experimental Neurology and Therapeutics, Hôspital de la Salpêtrière, 75013 Paris, France.
• J. Neurosci. 2004 Jun 30; 24 (26): 5922-30.

AbstractWe 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.

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