Polychlorinated biphenyl-stimulation of Ca(2+) oscillations in developing neocortical cells: a role for excitatory transmitters and L-type voltage-sensitive Ca(2+) channels.

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 Ca(2+). Acute exposure of cultures of newborn rodent cortical neurons to the commercial PCB mixture Aroclor 1254 [A1254; 1-20 microM (0.3-6 ppm)], induced recurring oscillations of intracellular Ca(2+) concentration (individual Ca(2+) amplitudes of 200-600 nM). This oscillatory activity was absent in control (0.5 mM Mg(2+)-containing) solution. Ca(2+) 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 Ca(2+) oscillation frequency and amplitude. Extracellular Ca(2+) entry via L-type voltage-sensitive Ca(2+) channels (VSCCs) was required to elicit the Ca(2+) oscillations because oscillations induced by A1254 were blocked in Ca(2+)-deficient solution or by addition of 1 microM nifedipine. Tetrodotoxin also blocked the Ca(2+) 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 Ca(2+) oscillations induced by A1254. After longer maintenance of the cells in vitro (7 days), A1254-induced Ca(2+) oscillations were selectively blocked by a combination of N-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.