ORTHO-SUBSTITUTED 2,2',3,5',6-PENTACHLOROBIPHENYL (PCB-95) ALTERS RATHIPPOCAMPAL RYANODINE RECEPTORS AND NEUROPLASTICITY IN-VITRO - EVIDENCE FOR ALTERED HIPPOCAMPAL FUNCTION

The effects of PCBs on hippocampal function were studied in vitro, by radioligand-receptor binding analysis and electrophysiological measure ments of the hippocampal slice preparation. [H-3]Ryanodine, a conforma tion-sensitive probe for ryanodine receptors, was employed to determin e how PCBs influence specific high-affinity occupancy to receptors fou nd in microsomes isolated from rat hippocampus. PCB 95 (2,2',3,5',6-pe ntachlorobiphenyl) exhibited a dose-dependent enhancement of [H-3]ryan odine receptor occupancy with an EC50 of 12 mu M. In contrast, PCB 66 (2,3',4,4'-tetrachlorobiphenyl) showed no activity toward ryanodine re ceptors, up to its solubility limit (greater than or equal to 200 mu M ) Population spike (PS) and excitatory postsynaptic potential (EPSP) r esponses were recorded from striatum pyramidale of the CA1 region, whi ch were generated from single pulse orthodromic stimulation of Schaffe r collateral/commissural (SC/C) fibers at striatum radiatum of the hip pocampal slice preparation. After the introduction of PCB 95 to the pe rfusion medium, PCB 95 depressed PS amplitude, especially at high stim ulus intensities. Significant reductions in PS and EPSP maxima were se en, even after induction of long term potentiation, a model of neuropl asticity. However, these actions were not observed with PCB 66 which l acks ryanodine receptor activity, implicating a ryanodine receptor-med iated mechanism in the general depression of pyramidal cell excitabili ty seen with PCB 95. Taken together, these results reveal a novel, ary lhydrocarbon (Ah) receptor-independent, mechanism by which PCB 95 alte rs neuronal Ca2+ signaling and neuroplasticity in adult brain. (C) 199 7 Inter Press, Inc.