Polychlorinated biphenyl-stimulation of Ca2+ oscillations in developing neocortical cells: A role for excitatory transmitters and L-type voltage-sensitive Ca2+ channels

Developmental exposure to polychlorinated biphenyls (PCBs), environmental t oxicants found throughout the world, results in neurodevelopmental delays a nd/or deficits. Previous mechanistic studies have demonstrated that PCBs el icit a broad spectrum of biochemical responses that include slow, graded in creases in intracellular Ca2+. Acute exposure of cultures of newborn rodent cortical neurons to the commercial PCB mixture Aroclor 1254 [A1254; 1-20 m u M (0.3-6 ppm)], induced recurring oscillations of intracellular Ca2+ conc entration (individual Ca2+ amplitudes of 200-600 nM). This oscillatory acti vity was absent in control (0.5 mM Mg2+-containing) solution. Ca2+ oscillat ions induced by a 1-h exposure to A1254 were concentration dependent, as me asured by cell recruitment (proportion of responding cells) as well as by C a2+ oscillation frequency and amplitude. Extracellular Ca2+ entry via L-typ e voltage-sensitive Ca2+ channels (VSCCs) was required to elicit the Ca2+ o scillations because oscillations induced by A1254 were blocked in Ca2+-defi cient solution or by addition of 1 mu M nifedipine. Tetrodotoxin also block ed the Ca2+ oscillations, suggesting that synaptic activity may activate VS CCs. To examine this further, the role of postsynaptic receptors that indir ectly activate L-type VSCCs was examined. At 4 to 5 days in vitro, when GAB A exerts a depolarizing action and activates L-type channels, addition of b icuculline blocked Ca2+ oscillations induced by A1254. After longer mainten ance of the cells in vitro (7 days), A1254-induced Ca2+ oscillations were s electively blocked by a combination of N-methyl-D-aspartate and non-N-methy l-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 ac tivation of excitatory GABAergic and/or glutamatergic synaptic activity, de pending on the stage of maturation.