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Updated: May 22, 2026
Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
Published on: August 15, 2017
Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development
Patrick A Forcelli1, Megan J Janssen, Stefano Vicini
1Interdisciplinary Program in Neuroscience, Georgetown University, School of Medicine, Washington, DC, USA. Paf22@georgetown.edu
Insights
Early exposure to certain antiepileptic drugs disrupts synaptic development in neonatal rats, potentially impacting long-term neurological function. Levetiracetam, however, did not show these adverse effects on synaptic maturation.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pharmacology
Background:
- Neonatal seizures require treatment, but early-life drug exposure poses risks to developing nervous systems.
- Antiepileptic drugs like phenobarbital are associated with neurotoxicity and neuronal apoptosis in animal models, raising concerns about functional outcomes.
Purpose of the Study:
- To investigate the impact of specific antiepileptic drugs on synaptic maturation in neonatal rats.
- To determine if proapoptotic actions of drugs correlate with impaired synaptic development.
- To assess the functional consequences of disrupted synaptic maturation.
Main Methods:
- Patch-clamp recordings were used to analyze synaptic maturation in striatal medium spiny neurons of neonatal rats.
- Rats were exposed to proapoptotic antiepileptic drugs (phenobarbital, phenytoin, lamotrigine) or a non-proapoptotic drug (levetiracetam).
- Behavioral assessments (reversal learning) were conducted in phenobarbital-exposed rats.
Main Results:
- Exposure to phenobarbital, phenytoin, or lamotrigine at postnatal day 7 prevented normal synaptic maturation between postnatal days 10-18.
- Phenobarbital exposure led to impaired behavioral performance at weaning.
- Melatonin pretreatment, which blocks apoptosis, prevented the disruption of synaptic maturation.
- Levetiracetam did not disrupt synaptic development.
Conclusions:
- First evidence that early-life antiepileptic drug exposure impairs synaptic maturation in surviving neurons.
- Suggests a mechanism linking early drug exposure to cognitive and behavioral deficits.
- Highlights the need for seizure therapies that preserve synaptic development.
Objective:
Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating 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.
Methods:
We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons 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.
Results:
Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and P18. 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 antiepileptic drugs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation.
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