Chronic Pb2+ exposure causes theta-band hypersynchrony disrupting sensory motor gating and exacerbating absence seizures

Abstract

ABSTRACTChronic lead (Pb2+) exposure from childhood contributes to an array of cognitive and behavioral dysfunctions including impaired attention and intellectual ability, learning and memory deficits, and delinquency. It is also an environmental risk factor for adult psychopathologies, most notably schizophrenia and epilepsy. 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 the developmental trajectory leading to a loss of parvalbumin-expressing interneurons in hippocampus and altered synaptic transmission. Little is known, however, about the impact of chronic Pb2+ exposure on hippocampal network dynamics which serve as a link between cellular-molecular effects and cognitive-behavioral consequences of Pb2+ neurotoxicity. Here, we tested the effects of chronic Pb2+ exposure on the hippocampal local field potential (LFP) of freely-behaving rats. Pb2+ exposure caused striking theta rhythmic hypersynchrony and heightened behavioral modulation of theta during locomotor behavior. Pb2+ exposure also markedly exacerbated absence seizures appearing in the LFP as spike-wave discharges with a theta-band fundamental frequency and strong theta-harmonic synchronization. Mechanisms of theta rhythmogenesis have been implicated in impairments of prepulse inhibition of the acoustic startle reflex (PPI), so we tested the effect of Pb2+ exposure on PPI in male and female rats at different developmental timepoints. We found that adult males (PN50 and 120), but neither females nor juvenile males showed reduced PPI independent of changes in the startle reflex. This pattern recapitulates sex- and age-dependencies of PPI disruption in schizophrenic patients. Overall, these results are consistent with the hypothesis that Pb2+ is an environmental risk factor for psychopathology in adulthood, especially those symptoms related to cognitive and sensory-motor gating processes that depend on rhythmic coordination of network activity in the hippocampus.