TY - JOUR T1 - Polychlorinated Biphenyl-Stimulation of Ca<sup>2+</sup>Oscillations in Developing Neocortical Cells: A Role for Excitatory Transmitters and L-Type Voltage-Sensitive Ca<sup>2+</sup>Channels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 105 LP - 113 VL - 295 IS - 1 AU - Jon R. Inglefield AU - Timothy J. Shafer Y1 - 2000/10/01 UR - http://jpet.aspetjournals.org/content/295/1/105.abstract N2 - Developmental exposure to polychlorinated biphenyls (PCBs), environmental toxicants found throughout the world, results in neurodevelopmental delays and/or deficits. Previous mechanistic studies have demonstrated that PCBs elicit a broad spectrum of biochemical responses that include slow, graded increases in intracellular Ca2+. Acute exposure of cultures of newborn rodent cortical neurons to the commercial PCB mixture Aroclor 1254 [A1254; 1–20 μM (0.3–6 ppm)], induced recurring oscillations of intracellular Ca2+ concentration (individual Ca2+ amplitudes of 200–600 nM). This oscillatory activity was absent in control (0.5 mM Mg2+-containing) solution. Ca2+ oscillations induced by a 1-h exposure to A1254 were concentration dependent, as measured by cell recruitment (proportion of responding cells) as well as by Ca2+ oscillation frequency and amplitude. Extracellular Ca2+ entry via L-type voltage-sensitive Ca2+ channels (VSCCs) was required to elicit the Ca2+ oscillations because oscillations induced by A1254 were blocked in Ca2+-deficient solution or by addition of 1 μM nifedipine. Tetrodotoxin also blocked the Ca2+oscillations, suggesting that synaptic activity may activate VSCCs. To examine this further, the role of postsynaptic receptors that indirectly activate L-type VSCCs was examined. At 4 to 5 days in vitro, when GABA exerts a depolarizing action and activates L-type channels, addition of bicuculline blocked Ca2+oscillations induced by A1254. After longer maintenance of the cells in vitro (7 days), A1254-induced Ca2+ oscillations were selectively blocked by a combination ofN-methyl-d-aspartate and non-N-methyl-d-aspartate receptor antagonists (d-2-amino-5-phosphonopentanoic acid and 2,3-dihydroxy-6,7-dinitroquinoxaline, respectively). These novel findings show the induction of network activity in an in vitro model by A1254 via activation of excitatory GABAergic and/or glutamatergic synaptic activity, depending on the stage of maturation. U.S. Government ER -