title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University, School of Medicine, Washington, DC, USA. Paf22@georgetown.edu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Forcelli
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Janssen
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
authors.forename: Karen
authors.initials: K
authors.lastname: Gale
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology* / Q000254:growth & development*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D053148:Caspase 3; C013411:biocytin; D008239:Lysine