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Epilepsia. 2018 Feb;59(2):333-344. doi: 10.1111/epi.13990. Epub 2018 Jan 5.

Neonatal phenobarbital exposure disrupts GABAergic synaptic maturation in rat CA1 neurons.

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Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.
Department of Neuroscience, Georgetown University, Washington, DC, USA.



Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. The use of phenobarbital continues despite growing evidence that it exerts suboptimal seizure control and is associated with long-term alterations in brain structure, function, and behavior. Alterations following neonatal phenobarbital exposure include acute induction of neuronal apoptosis, disruption of synaptic development in the striatum, and a host of behavioral deficits. These behavioral deficits include those in learning and memory mediated by the hippocampus. However, the synaptic changes caused by acute exposure to phenobarbital that lead to lasting effects on brain function and behavior remain understudied.


Postnatal day (P)7 rat pups were treated with phenobarbital (75 mg/kg) or saline. On P13-14 or P29-37, acute slices were prepared and whole-cell patch-clamp recordings were made from CA1 pyramidal neurons.


At P14 we found an increase in miniature inhibitory postsynaptic current (mIPSC) frequency in the phenobarbital-exposed as compared to the saline-exposed group. In addition to this change in mIPSC frequency, the phenobarbital group displayed larger bicuculline-sensitive tonic currents, decreased capacitance and membrane time constant, and a surprising persistence of giant depolarizing potentials. At P29+, the frequency of mIPSCs in the saline-exposed group had increased significantly from the frequency at P14, typical of normal synaptic development; at this age the phenobarbital-exposed group displayed a lower mIPSC frequency than did the control group. Spontaneous inhibitory postsynaptic current (sIPSC) frequency was unaffected at either P14 or P29+.


These neurophysiological alterations following phenobarbital exposure provide a potential mechanism by which acute phenobarbital exposure can have a long-lasting impact on brain development and behavior.


apoptosis; cell death; gestational; neonatal; patch-clamp; teratogen

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