Vulnerability of synapses in the frontal cortex of mice developmentally exposed to an insecticide: Potential contribution to neuropsychiatric disease

Abstract

Increasingly, exposure to various chemicals found in our environment has been found to be a significant contributor to the risk of developing neurological disease, such as Parkinson disease, autism spectrum disorder, as well as other deficits in thought and function. Exposure to these compounds during critical periods of neurodevelopment, encompassing exposures that occur in utero, during infancy, childhood, and adolescence, represents a time period of nervous system growth that is uniquely vulnerable to disruption by environmental chemicals. Indeed, a contemporary hypothesis suggests that the pathological cascade associated with many common neurological disorders has its origin in disturbances of normal neurodevelopment. Moreover, alterations to the ontogeny of the synapse and neurotransmitter signaling during neurodevelopment may be a premier pathological event that underlies neuropsychiatric and neurodegenerative disease. To interrogate the impact of exposure to a ubiquitous environmental chemical, the pesticide, endosulfan, on development of neurotransmitter circuits, we coupled in vitro and in vivo platforms to evaluate its effect on the formation of GABAergic, glutamatergic, and dopaminergic pathways in the frontal cortex. With this approach we found exposure of cortical neurons, in vitro, exhibited a marked reduction in the length of their neurite process as well as the number of synaptic connections. Further investigation using an in vivo model of developmental exposure identified significant alterations to pre and postsynaptic proteins involved in neurotransmitter handling and signaling in each of the neurotransmitter systems investigated. These findings suggest that exposure to endosulfan during vulnerable periods of neurodevelopment can alter the normal development and potential function of neurotransmission in the frontal cortex. Interestingly, the alterations identified in our study closely mimic the pathological markers associated with schizophrenia, which shows disturbances in synaptic proteins important for GABAergic, glutamatergic, and dopaminergic signaling in the frontal cortex. These findings provide important support for the impact of exposure to environmental chemicals during neurodevelopment and risk for neurological disease.