Epidemiological studies indicate that developmental exposure to polychlorinated biphenyls (PCBs) represents a significant risk factor affecting parameters of learning and cognition in humans. Our long term objective is to understand exactly how the major ortho-substituted PCBs found in human tissues and their metabolites alter spatial and temporal aspects of Ca2+ signaling in neurons of hippocampus and how these mechanisms relate to alterations in (1) synaptic plasticity and (2) associative learning and memory. The specific goals of this pilot proposal focus on understanding how PCB170 (2,2',3,3',4,4',5-heptachlorobiphenyl), a major contaminant of human tissues, affects neurodevelopmental toxicity in rats. Preliminary work has revealed that PCB170 is one of the most potent modulators of the ryanodine receptor (RyR2)/immunophilin (FKBP12) Ca2+ channel complex which predominates within hippocampal neurons. Since the RyR2/FKBP12 complex regulates important aspects of neuroplasticity and has been shown to be closely associated with acquisition of spatial learning, the following hypotheses will be tested: HYPOTHESIS I: PCB170 is a potent modulator of the RyR2/FKBP12 complex of primary hippocampal neurons, an activity which alters short-term (functional) and long-term (transcriptional) Ca2+ signaling critical for neuroplasticity.
The specific aims are to elucidate: (1) the molecular mechanism(s) by which PCB170 alters the fidelity of neuronal Ca2+ signaling in cultured hippocampal neurons, (2) whether PCB170 alters expression of key proteins involved in Ca2+-dependent signaling, especially the RyR2/FKBP12 complex, whose activity is known to be associated with changes in neuroplasticity of hippocampus, and (3) if perinatal exposure to PCB170 in vivo alters normal developmental expression of the RyR2/FKBP12 complex in hippocampus, and its relationship to induction of long term potentiation. (Year 1) HYPOTHESIS II: Perinatal exposure to PCB170 alters acquisition of hippocampal associative learning, an effect which is closely correlated with perturbations in the function and transcriptional induction of the RyR2/FKBP12 complex in CA1, CA3 and dentate gyrus.
The specific aims are to determine if perinatal exposure to PCB170: (1) alters spatial learning in the Morris water maze and (2) alters the normal relationship between acquisition of spatial learning and transcriptional induction of the RyR2/FKBP 12 complex. (Year 2)
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| Pessah, I N; Beltzner, C; Burchiel, S W et al. (2001) A bioactive metabolite of benzo[a]pyrene, benzo[a]pyrene-7,8-dione, selectively alters microsomal Ca2+ transport and ryanodine receptor function. Mol Pharmacol 59:506-13 |
| Wong, P W; Garcia, E F; Pessah, I N (2001) ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism. J Neurochem 76:450-63 |
