Lasting Increases in Neuronal Activity and Serotonergic Receptor Expression Following Gestational Chlorpyrifos Exposure

Abstract

Perinatal exposure to the organophosphorus insecticide chlorpyrifos (CPF) is associated with an increased incidence of neurodevelopmental disorders, such as autism spectrum disorder. While these behavioral detriments have been modeled in rodents, the underlying functional alterations in the developing brain are largely unknown. Previous reports using a rat model have identified alterations to both inhibitory synaptic transmission and serotonergic (5-HT) receptor binding in the cortex following developmental CPF exposure. Here, we use a rat model of gestational CPF exposure to investigate whether this altered inhibitory activity is driven by increased spontaneous firing of inhibitory interneurons and altered 5-HT receptor expression. Using cell-attached ex vivo electrophysiology in young rats of both sexes, we identified a significant increase in the number of spontaneously firing neurons in the somatosensory cortex of CPF-exposed offspring. Analysis of action potential metrics identified a sub-set of these neurons as fast-spiking parvalbumin (PV) interneurons. Immunohistochemical labeling of c-Fos, a marker of neuronal activity, further revealed a pronounced increase in activity of neurons of the somatosensory cortex in both juvenile and adult rats that had been gestationally exposed to CPF. Finally, RNAscope in situ hybridization showed an increase in the expression of the inhibitory receptor 5-HT1B in PV neurons. The data here demonstrate that gestational exposure to CPF results in persistent hyper-excitation of the somatosensory cortex, potentially through increased expression of the receptor 5-HT1B and resulting disinhibition. These neurophysiological effects may contribute to the established behavioral outcomes resulting from gestational exposure to CPF and offer guidance for novel preventative interventions. SIGNIFICANCE STATEMENTWe report persistent increases in spontaneous neuronal firing in the somatosensory cortex following a brief gestational exposure to the organophosphorus insecticide CPF in rats. This occurred in conjunction with increased expression of the 5-HT1B receptor measured specifically in PV interneurons. The hyper-excitability of the somatosensory cortex described here agrees with the established hyper-sensitivity to sensory stimulation seen in neurodevelopmental disorders such as autism spectrum disorder. These results offer a possible mechanistic framework underlying the neurophysiological effects associated with early life exposures to the organophosphorus insecticide CPF.