Abstracts

Rationale: Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. Additionally, the side effects of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the NINDS epilepsy research benchmarks call for the implementation of standardized protocols for screening ASDs for their amelioration or exacerbation of cognitive comorbidities. Long-term potentiation (LTP) is a widely used model for investigating synaptic plasticity and its relationship to learning and memory. While the effects of some (but not all) ASDs on LTP have been examined, none of these studies employed physiologically relevant induction stimuli such as theta-burst stimulation (TBS) or examined the effects of ASDs on brain regions beyond area CA1 of the rodent hippocampus. To address this paucity of data, we examined the effects of a broad representation of existing ASDs on TBS-induced LTP in both area CA1 and the dentate gyrus of C57BL/6 mice. Methods: Coronal brain slices (350 μm) containing the dorsal hippocampus were made. Recordings were obtained from four slices at a time using the Scientifica Slicemaster high throughput recording system. Slices exposed to ASDs were paired with slices from the opposite hemisphere; these served as controls. Field excitatory post-synaptic potentials (fEPSPs) were recorded in response to stimuli set to 50% of their maximum. All ASDs were applied to slices by bath perfusion for 20 minutes prior to the induction stimulus. LTP was induced by TBS (4 trains of 4 pulses at 100 Hz separated by 200 ms and repeated once with a 20 s interval) or by high-frequency stimulation (HFS: 100Hz/1sec). The following ASDs were examined: phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), topiramate (TPM), lamotrigine (LTG), levetiracetam (LEV), retigabine (RTG), and tiagabine (TGB). Results: Among known voltage-gated sodium channel inhibitors, 60μM LTG failed to affect plasticity, 50μM CBZ significantly attenuated TBS-induced LTP (39.4±12.3% of matched controls, p<0.01), and 80μM PHT attenuated both TBS-induced LTP (54.6±16.3% of matched controls, p<0.05) and post-tetanic potentiation (PTP). 10μM RTG failed to affect LTP but did significantly affect PTP. 600µM VPA failed to affect LTP in area CA1, both in C57BL/6 mice and Sprague Dawley rats, using TBS or HFS. However, 600µM VPA did attenuate TBS-induced LTP in the dentate gyrus (46.4±11.2% of matched controls, p<0.05). Conclusions: The experiments performed here comprehensively examined the effects of the most commonly used ASDs on the preeminent in-vitro model of learning and memory while, for the first time, using physiologically relevant protocols. These results establish a foundational knowledge of ASD effects on LTP in the hippocampus and will ultimately be used to validate the predictive value of TBS induced LTP for cognitive impairments associated with novel ASDs. Supported by NINDS (Contract # 271201100029C) and the Interdepartmental Neuroscience Program at the University of Utah.