Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development

Abstract

Objective Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating of infants. This is of particular concern for treating neonatal seizures, as early-life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis. Method We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons (MSNs) from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning. Result Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and 18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development. Interpretation Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early-life exposure to AEDs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation.

The Krushinsky-Molodkina rat strain: The study of audiogenic epilepsy for 65 years

“…Our data (not presented) concerning modulation of AS and postictal catalepsy by haloperidol injections, as well as data from the literature, e.g., [37], confirm such complicated interactions even during development [38]. In KM rats, the striatum DA system was shown to be different from that in rats of nonaudiogenic prone groups.…”

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

“…Several animal studies are suggestive of hydantoin being a DNT toxicant. Described effects range from impaired synapse function (Forcelli et al, 2012) and neurodegeneration (Asimiadou et al, 2005) to general neurotoxicity (Hatta et al, 1999). However, the studies fail to fulfill the full set of criteria defined by the workshop participants for a DNT reference compound (Box 2, Tab.…”

Breast is Still Best: No Harmful Effects of Breastfeeding in Women Taking Antiepileptic Drugs

“…The few reports that examine the effects of AEDs on the early postnatal brain demonstrate neuron cell death, disruptions in synapse formation, and behavioral deficits (7,8). However, animal studies use therapeutic doses, not the subtherapeutic levels expected to be present in milk, and they do not control for the non-nursing condition.…”