Gestational Chlorpyrifos Exposure Imparts Lasting Alterations to the Rat Somatosensory Cortex

Abstract

Chlorpyrifos is an organophosphorus pesticide used extensively in agricultural and residential settings for nearly 60 years. Gestational, sub-acute exposure to chlorpyrifos is linked to increased prevalence of neurodevelopmental disorders. Animal studies have modeled these neurobehavioral detriments, however, the functional alterations in the brain induced by this exposure remain largely unknown. To address this, we used a rat model of gestational chlorpyrifos exposure to interrogate the alterations in the developing somatosensory (barrel) cortex. Rat dams were exposed to chlorpyrifos (5 mg/kg) or vehicle on gestational days 18-21 via subcutaneous injection, with no overt acute toxicity. Acetylcholinesterase was modestly inhibited but returned to baseline levels by postnatal day 12. We performed whole-cell patch clamp recordings on postnatal days 12-20 in both male and female progeny of the treated dams. A spike timing dependent plasticity protocol revealed changes to the normal development of use-dependent plasticity, including interference in long-term synaptic depression. Recording inhibitory synaptic activity revealed an increase in the frequency of spontaneous postsynaptic currents and in paired pulse ratios, in conjunction with a significant decrease in miniature postsynaptic currents. These findings suggest a presynaptic mechanism of inhibited GABA release, with potential disinhibition of inhibitory neurons. Evaluation of barrel cortex development displayed disruptions to normal barrel field patterning, with increases in both the septal area and total barrel field. We provide evidence for functional and structural alterations during brain development induced by in utero exposure to the organophosphorus pesticide chlorpyrifos that may account for the well-established behavioral outcomes. SIGNIFICANCE STATEMENTWe demonstrate persistent alterations to synaptic function and plasticity in the somatosensory cortex following a brief, sub-acute exposure to the organophosphorus pesticide chlorpyrifos in a gestational rat model. These occur in conjunction with structural changes to cellular patterning of this brain region. These previously unknown consequences are potential causal mechanisms to the well-established neurodevelopmental detriments associated with early life exposure to chlorpyrifos. Clarifying these mechanisms could aid in ameliorating or preventing their persistent effects.