Evidence suggests significant involvement of environmental factors in the pathogenesis of autism spectrum disorders (ASDs) but specific environmental contaminants that increase risk of ASDs, severity and/or treatment outcome remain to be identified. Recent human studies link exposure to organophosphorus pesticides (OPs) with ASDs;however, a biological mechanism supporting that link has yet to be described. Genetic, histological and functional imaging data implicate altered patterns of synaptic connectivity in ASD pathology. The neurexin (NRXN)-neuroligin (NLG)-SHANK signaling pathway is critically important in regulating synaptic connectivity, and NLG mutations are genetic risk factors for ASD. Neuroligin shares sequence, structural and functional homology with acetylcholinesterase, an established molecular target of OPs, suggesting that neuroligins may also be a target for OPs. Based on these observations, I hypothesize that exposure of the developing brain to OPs alters synaptic connectivity by interfering with neuroligin-mediated synapse formation, stabilization and/or functional plasticity, and this effect is exacerbated by ASD-linked mutations in the NLG genes that encode neuroligin. To test this novel hypothesis, I will adapt an in vitro model developed during discovery of the role of neuroligins in synaptic connectivity to address the following aims: (1) Determine whether OPs interfere with neuroligin-mediated synaptic connectivity in primary cultures of hippocampal neurons at the level of synapse density, the ratio of excitatory to inhibitory synapses and synaptic function;and (2) Determine whether expression of NLG mutations associated with ASDs exacerbate the effects of OPs on synaptic connectivity in vitro. I expect that OPs, at concentrations that do not inhibit acetylcholinesterase, will alter the number of synapses formed by cultured hippocampal neurons, which will create an imbalance of excitatory to inhibitory synapses and alter both spontaneous and evoked neuronal electrical activity. These studies will provide new mechanistic information about how OPs and NLG mutations converge to promote adverse neurodevelopmental outcomes of relevance to ASDs, and will identify a biological mechanism to corroborate human studies linking OP exposure to increased risk for ASDs. The identification of OPs as environmental risk factors for ASD will provide a rational mechanism for preventing the incidence of ASD and/or decreasing the severity of clinical symptoms by controlling exposures to OPs during critical periods of neurodevelopment.
There is growing consensus that environmental factors significantly influence the risk, severity and/or treatment outcomes of autism spectrum disorders (ASDs) but specific environmental contaminants associated with ASDs remain to be identified. Recent human studies link exposure to organophosphorus pesticides (OPs) to increased ASD risk;however, a biological mechanism supporting this link has yet to be described. Clinical and experimental evidence suggests that the clinical symptoms of ASD reflect altered patterns of synaptic connectivity;therefore, I will test the highly innovative hypothesis that OPs alter synaptic connectivity by interfering with the function of neuroligins, a class of membrane proteins that regulate synapse stability and plasticity, and this adverse interaction is amplified y mutations in neuroligin associated with increased ASD risk.
|Harrill, Joshua A; Chen, Hao; Streifel, Karin M et al. (2015) Ontogeny of biochemical, morphological and functional parameters of synaptogenesis in primary cultures of rat hippocampal and cortical neurons. Mol Brain 8:10|