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bioRxiv · 10.1101/2020.06.30.181149

Chronic lead exposure causes theta and gamma hypersynchrony in the hippocampus and disrupts sensorimotor gating

Schultheiss, N. W.·McGlothan, J. L.·Guilarte, T. R.·Allen, T. A.
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Abstract

Chronic early-life lead (Pb2+) exposure contributes to an array of cognitive and behavioral dysfunctions, including impaired attention, memory, and intellectual abilities, in addition to increased social delinquency. Notably, Pb2+ exposure is an environmental risk factor for adult psychopathologies, including schizophrenia and epilepsy. Neurobiologically, Pb2+ is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, and exposure during early life elicits a cascade of cellular neurotoxic effects that alter neurodevelopmental trajectories. This includes reduced parvalbumin-expressing interneurons in the hippocampus (HC) and altered synaptic transmission. Little is known, however, about the impact of chronic Pb2+ exposure on HC network dynamics, which link cellular-molecular effects with cognitive-behavioral consequences. Here, we tested the impact of chronic Pb2+ exposure on the HC local field potential (LFP) in freely behaving rats. We found that Pb2+ exposure (1) caused a striking level of theta rhythmic hypersynchrony, (2) amplified fast gamma synchronization, (3) disrupted behavioral modifications of theta and fast gamma, and (4) exacerbated absence seizures appearing in the LFP as spike-wave discharges (SWDs) at theta frequencies. Each of these rhythmic changes in the HC network was related to exploratory movements in the open field. HC network alterations like these have also been linked to impaired prepulse inhibition of the acoustic startle reflex (PPI). Thus, next, we tested the effect of Pb2+ exposure on PPI. We found that adult males (PN50 and 120), but neither females nor juvenile males, showed reduced PPI, recapitulating sex dependencies on PPI disruptions in schizophrenics. Altogether, these results are consistent with the hypothesis that chronic early-life Pb2+ exposure causes dysfunction in the rhythmic network coordination of the HC, limiting processing, and helping to account for cognitive deficits.

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Schultheiss, N. W., McGlothan, J. L., Guilarte, T. R., Allen, T. A.. 2020-07-02. Chronic lead exposure causes theta and gamma hypersynchrony in the hippocampus and disrupts sensorimotor gating. https://doi.org/10.1101/2020.06.30.181149

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