Ortho-substituted 2,2',3,5',6-pentachlorobiphenyl (PCB 95) alters rat hippocampal 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 measurements of the hippocampal slice preparation. [³H]Ryanodine, a conformation- sensitive probe for ryanodine receptors, was employed to determine how PCBs influence specific high-affinity occupancy to receptors found in microsomes isolated from rat hippocampus. PCB 95 (2,2',3,5',6-pentachlorobiphenyl) exhibited a dose-dependent enhancement of [³H]ryanodine receptor occupancy with an EC₅₀ of 12 μM. In contrast, PCB 66 (2,3',4,4'-tetrachlorobiphenyl) showed no activity toward ryanodine receptors, up to its solubility limit (≤200 μM). Population spike (PS) and excitatory postsynaptic potential (EPSP) responses were recorded from striatum pyramidale of the CA1 region, which were generated from single pulse orthodromic stimulation of Schaffer collateral/commissural (SC/C) fibers at striatum radiatum of the hippocampal slice preparation. After the introduction of PCB 95 to the perfusion medium, PCB 95 depressed PS amplitude, especially at high stimulus intensities. Significant reductions in PS and EPSP maxima were seen, even after induction of long term potentiation, a model of neuroplasticity. However, these actions were not observed with PCB 66 which lacks ryanodine receptor activity, implicating a ryanodine receptor-mediated mechanism in the general depression of pyramidal cell excitability seen with PCB 95. Taken together, these results reveal a novel, arylhydrocarbon (Ah) receptor-independent, mechanism by which PCB 95 alters neuronal Ca²⁺ signaling and neuroplasticity in adult brain.