Abstracts

Rationale: Early life seizures (ELS) are often associated with mental retardation, learning and memory deficits in adulthood and post-neonatal epilepsy. Functional studies of the effects of ELS on the brain later in life often focus on the hippocampus, fewer studies have looked into functional changes in the neocortex. The medial prefrontal cortex (mPFC) is a particularly attractive target for future studies into the effect of ELS on the neocortex. This is because of its strong reciprocal connections to the hippocampus and well-documented role in mediating tasks that require learning, memory and attention, functions that are thought to be involved in cognitive deficits seen in adults and adolescents who have experienced neonatal seizures. PFC synapses, like those in the hippocampus, show a substantial amount of plasticity both long- and short-term. Short-term plasticity (STP) in the PFC is thought to be a molecular correlate of short term working memory, and may have a role in attention. This study examines STP in a layer- and frequency- dependent manner in order to determine the long-lasting consequences of ELS on PFC function.Methods: Sprague-Dawley rat pups received a total of 65 flurothyl seizures from postnatal day (P)6 to P17. Extracellular field potentials evoked in LII or LV of the prelimbic region of the mPFC were recorded in LV in ELS (N=3) and littermate controls (N=3) at P27-P36. The frequency dependence of short-term post-tetanic potentiation (PTP) in LII-LV circuits and LV-LV circuits was probed using a baseline single test pulse stimulation delivered repeatedly at 0.1Hz (low baseline) or 0.5Hz (high baseline) and a 50Hz tetanus, 15 pulses, delivered one time. In addition to PTP, paired pulse facilitation was assessed at interpulse intervals varying from 6 ms (150 Hz) to 200 ms (1.7Hz). Stimulus number dependent plasticity was also assessed through examination of the fEPSP during 50 Hz stimulation. Results: In ELS animals, we found a significant increase in PTP in LII-LV circuits under the low baseline stimulation paradigm, alongside a significant decrease in stimulus number dependent plasticity in LV-LV connections (p<0.01, two-way repeated measures ANOVA). No change was noted in PTP with high baseline stimulation in LII-LV, or in LII-LV stimulus number dependent plasticity. PTP in LV-LV connections was also unaffected by ELS. It should also be noted that LII-LV facilitation was slightly increased in the ELS group (ns). Conclusions: The PFC is a critically important but vastly understudied brain region in the field of early life epilepsy research. While traditionally research has focused on the hippocampus, recent evidence indicates that alterations in PFC circuitry may also be responsible for some ELS-induced behavioral deficits. The results presented further our understanding of the deleterious neurodevelopmental consequences of ELS on the PFC by showing long-lasting changes in STP. In the future, this knowledge can be used to develop targeted drug therapy to ameliorate some of the cogntive deficits of ELS. This work was supported by NIH Grants RO1NS056170 and RO1NS041595.