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Abstract
Antiepileptic drugs (AEDs) are first-line seizure treatments. Despite use in pregnancy and early life, their impact on brain maturation is unclear. This can only be assessed in preclinical models (e.g., rats), as seizures and AEDs are inextricably linked in patients. Previous studies revealed enhanced neuronal apoptosis (ENA) in neonatal (postnatal day (P)7-14) rats (corresponding to late third trimester/infancy in humans), following therapeutic doses of some AEDs. It is not known if ENA is associated with, or predictive of, functional changes. To test the hypothesis that AED exposure per se would alter brain maturation/function, pups were exposed to AEDs that do [phenobarbital (PB), phenytoin (PHT)] or do not [lamotrigine (LTG), carbamazepine (CBZ), levetiracetam (LEV)] induce ENA, and later-life histological, physiological, and behavioral outcomes were assessed. Limbic regions regulating emotion, memory, and relevant to psychiatric findings in patients with early-life AED-treated seizures, have not been assessed for ENA. Therefore, P7 rats exposed to PB, PHT, or CBZ, were evaluated on P8 for ENA. PB and PHT, but not CBZ induced ENA in limbic regions. The striatum, vital for motor and cognitive function, is particularly vulnerable to ENA. To determine if AED exposure (on P7) altered synaptic maturation, patch-clamp recordings were made from striatal neurons (P10-P18). Inhibitory and excitatory postsynaptic current frequency significantly increased from P10 to P18 in controls; this maturation was disrupted by PB, PHT, or LTG but not by LEV. Behavioral outcomes after PB, PHT, and LTG exposure (P7-14) were assessed in adulthood (P60+). Disruptions in motor function (PHT, LTG), emotional/social behavior (PB, LTG), learning/memory (PB, PHT, LTG), sensorimotor gating (PB), and seizure threshold (PHT) were detected. Deficits in reversal learning and enhanced amphetamine-induced locomotion were detected in P25 rats exposed to PB on P7. These results indicate that early (P7 to P14) exposure to certain AEDs impedes later synaptic maturation and behavioral functions. ENA induction does not correlate with adverse outcomes, suggesting AEDs disrupt brain maturation even without killing neurons. These findings share features with human psychiatric disorders, suggesting that AEDs must be considered as a contributor to the long-term adverse clinical outcomes in infants experiencing early-life seizures.
