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NERVOUS SYSTEM CELL BIOLOGY

Dopamine induces apoptosis in young, but not in neonatal, neurons via Ca²⁺-dependent signal

¹Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, and Department of Medicine (Cardiology), New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and ²Cardiovascular Research Institute and ³Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Submitted 5 March 2007 ; accepted in final form 20 August 2007

Dopamine signaling plays a major role in regulation of neuronal apoptosis. During the postnatal period, dopamine signaling is known to be dramatically changed in the striatum. However, because it is difficult to culture neurons after birth, little is known about developmental changes in dopamine-mediated apoptosis. To examine such changes, we established the method of primary culture of striatal neurons from 2- to 3-wk-old (young) mice. Dopamine, via D₁-like receptors, induced apoptosis in young, but not neonatal, striatal neurons, suggesting that the effect of dopamine on apoptosis changed with development. In contrast, although isoproterenol (Iso), a β-adrenergic receptor agonist, increased cAMP production to a greater degree than dopamine, Iso did not increase apoptosis in striatal neurons from young and neonatal mice, suggesting a minor role of cAMP in dopamine-mediated apoptosis. Next, we examined the effect of dopamine on Ca²⁺ signaling. Dopamine, but not Iso, markedly increased intracellular Ca²⁺ in striatal neurons from young mice, and Ca²⁺-chelating agents abolished dopamine-induced apoptosis, suggesting that Ca²⁺ played a major role in the dopamine-mediated apoptosis pathway. In contrast, dopamine failed to increase intracellular Ca²⁺ in neonatal neurons, and the expression of PLC, which can increase intracellular Ca²⁺ via D₁-like receptor activation, was significantly greater in young than in neonatal striatal neurons. These data suggest that the developmental change in dopamine-mediated Ca²⁺ signaling was responsible for differences between young and neonatal striatum in induction of apoptosis. Furthermore, the culture of young striatal neurons is feasible and may provide a new tool for developmental studies.

neuronal culture; phospholipase C; striatum; adenosine 3',5'-cyclic monophosphate