All procedures were approved by the Georgetown University Animal Care and Use Committee.
Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development†
Version of Record online: 11 MAY 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 3, pages 363–372, September 2012
How to Cite
Forcelli, P. A., Janssen, M. J., Vicini, S. and Gale, K. (2012), Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol., 72: 363–372. doi: 10.1002/ana.23600
- Issue online: 2 OCT 2012
- Version of Record online: 11 MAY 2012
- Accepted manuscript online: 29 MAR 2012 06:19AM EST
- Manuscript Accepted: 23 MAR 2012
- Manuscript Revised: 5 MAR 2012
- Manuscript Received: 2 NOV 2011
- Epilepsy Foundation (P.A.F.)
- NIH/NINDS. Grant Number: F31NS066822 (P.A.F.)
- NIH/NIMH. Grant Numbers: R21MH079991 (K.G.), R01MH64797 (S.V.)
- NIH/NIDA. Grant Number: T32DA007291 (P.A.F., M.J.J.)
- NIH/NINDS. Grant Number: T32NS041231 (P.A.F.)
- GlaxoSmithKline provided a research grant (K.G., P.A.F.) and lamotrigine
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.
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.
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.
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. ANN NEUROL 2012;72:363–372