GABA is the main inhibitory neurotransmitter in the adult brain. GABA/A receptors, composed of multiple subunits, are structurally linked to C1- channels. These receptors mediate the inhibitory actions of GABA by causing C1-influx resulting in hyperpolarization. Organochlorine pesticides block functions of these receptors in insects and vertebrates by acting as competitive antagonists at the GABA binding site (cyclodienes) or binding directly to the C1- channel (lindane). GABA acts as a trophic signal for developing neurons, and may also influence the expression of its own receptors during brain development. The working hypothesis is that the ability of organochlorines to specifically target GABA/A receptors may make the developing nervous system especially vulnerable to these neurotoxins. This hypothesis will be tested using in vivo and in vitro models to determine whether exposure to organochlorine pesticides alters developmental expression of GABA/A receptors, receptor function, or development of cells that express these receptors (GABA-receptive cells). For our in vivo model, pesticides will be administered to pregnant rats followed by quantitative PCR to analyze levels of mRNA transcripts encoding GABA/A receptor subunits in brains of embryos, neonates and postnatally developing offspring. Quantitative in situ hybridization will then be used to allow a more detailed analysis of region-specific effects. Receptor function will be evaluated by 36/C1- flux assays. If pesticides alter receptor expression or function, primary cultures will be produced from embryonic brain regions where such effects are found. These cultures will be evaluated as an appropriate in vitro model to allow rapid analysis of the direct effects of pesticides on GABA/A receptor expression, function, and development of GABA-receptive cells. These studies will provide important information regarding the possibility that organochlorine pesticides may pose a risk to the developing brain by virtue of their ability to alter expression or function of GABA/A receptors.
| Liu, J; Morrow, A L; Devaud, L et al. (1997) GABAA receptors mediate trophic effects of GABA on embryonic brainstem monoamine neurons in vitro. J Neurosci 17:2420-8 |
