Abstracts

Rationale: There is a well-described association between autism and epilepsy, but the mechanisms underlying this association remain unclear. It is hypothesized that the epileptiform discharges that occur in approximately 50% of children with autism are important for understanding the disorder but the precise role of these discharges has yet to be explored. Methods: In order to understand the relationship between frequent epileptic discharges during the neurodevelopmental period and cognition later in life, a robust model of focal prefrontal cortical interictal spikes without overt seizures is required. No model of this type has yet been reported. To this end, we developed a model in which we gave p21 rat pups intracortical injections (0.5μL) of 175 μM bicuculline methiodine in normal saline whilst continuously recording EEG. Within seconds of injection, robust focal spikes were recorded at the injection site without behavioral seizures. The injections were repeated in order to achieve 5 days of epileptic activity in the absence of seizures, mimicking the prolonged aberrant activity seen in 50% of autistic children. With this model in place, we were able to test the effects of early life epileptiform activity (ELEA) on network-level changes in short-term synaptic plasticity in the PFC that are associated with PFC function. Extracellular field potentials evoked in LII or LV of the prelimbic region of the mPFC were recorded in layer V in ELEA and littermate control animals at P27-P36. 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 and a 50Hz tetanus, 15 pulses, delivered one time. Paired pulse facilitation was assessed at interpulse intervals varying from 10 ms (100 Hz) to 400 ms (2.5Hz). Stimulus number plasticity was also assessed through examination of the fEPSP during 50-Hz stimulation. Results: In ELEA animals (N=5, N=5 controls), we found a significant increase in PTP in the LII-LV network, with a small but not significant increase in the LV-LV network. Facilitation and stimulus number dependent plasticity were not significantly different in ELEA animals than controls. Conclusions: These changes mimic alterations that we have recently observed after early life seizures and may represent a network-level mechanism for cognitive deficits seen in children with a history of epileptiform activity. Studies are ongoing to test whether or not ELEA animals also have behavioral deficits that mimic early life seizure animals.