Abstracts

Rationale: Childhood exposure to lead (Pb2+) can cause cognitive and behavioral dysfunctions that manifest during adolescence and young adulthood, and Pb2+ exposure is a likely risk factor for endophenotypes of epilepsy and schizophrenia later in life. Given the overlap between critical early phases of brain development and the postnatal time-course of blood-brain barrier maturation, the youngest children are most vulnerable to Pb2+ exposure despite the latency at which dysfunction may develop. Patients acutely exposed to high levels of Pb2+ frequently present clinically with seizure, but the effects of consistent early-life exposure to low levels of Pb2+ remain to be clarified. Animal models that recapitulate cognitive and behavioral effects of Pb2+ exposure have identified the reduction of parvalbumin-expressing GABAergic interneurons, altered NMDA receptor composition, and disruption of neurotransmitter release dynamics as important cellular substrates of dysfunction; but the functional consequences of these cellular effects for network activity and circuit dynamics are not known.

Methods: We made simultaneous electroencephalographic recordings using 32 channel probes (NeuroNexus and handmade) implanted in hippocampus (HC) and prefrontal cortex (PFC) of freely-behaving rats (n=10). Analysis of EEG data was performed using custom functions for signal processing and spectral analyses (Matlab; MathWorks, Natick, MA).

Results: We found that chronic Pb2+ exposure from early life (1) elevated baseline theta- and gamma-band synchronization during behavioral engagement, while (2) disrupting behavioral modulation of theta and gamma rhythmogenesis. During epochs of behavioral quiescence, (3) Pb2+ exposure exacerbated the incidence and intensity of absence seizures characterized by highly-stereotyped, large-amplitude spike-wave discharges (SWDs) in both PFC and HC. Echoing theta-gamma hypersynchrony during behavior, SWDs uniformly exhibited a theta-band fundamental frequency, and theta power during seizures reached or exceeded maximal values observed during fast locomotion for each animal. Absence seizures were completely eliminated by ethosuximide (50-200 mg/kg).

Conclusions: Together our findings indicate that chronic low level Pb2+ exposure during early life (1) elevates the epileptogenic potential of locally-coupled neuronal networks, (2) reduces the dynamic range of behavioral encoding, and (3) is a significant risk factor for absence epilepsy in a well-established rodent model. Our findings suggest that dysfunctions resulting from Pb2+ exposure may be mediated either by baseline effects on neural synchronization or by the incidence of absence seizures. Furthermore, some neurostimulation protocols or antiepileptic drug regiments may be efficacious for ameliorating cognitive and behavioral effects of Pb2+ neurotoxicity.

Funding: R01 MH13626 to TA Allen