Learning and memory differently impaired by anti-seizure drugs

University of Utah researchers have discovered that certain classes of anti-seizure drugs (ASDs) modulate long-term potentiation (LTP) through different mechanisms.

Previous research has already shown that common side-effects of ASDs – used to treat temporal lobe epilepsy – included cognitive disturbances (e.g. learning and memory). However, new results published in Epilepsia used theta-burst stimulation (TBS) to examine how ASDs affect LTP and post-tetanic potentiation (PTP) by mimicking physiologically relevant stimuli.

Principal Investigator Professor H. Steve White, lead author Dr Peter West and their team from the Anticonvulsant Drug Development Program used Scientifica’s SliceMaster high throughput recording system to record field excitatory postsynaptic potentials (fEPSPs) from four coronal brain slices simultaneously.

They made slices containing the dorsal hippocampus in either standard or sucrose-based ACSF. Tests carried out on two slices investigated the effects of an ASD while the other two served as controls (obtained from the same animal).

ASDs were applied through bath perfusion for 20 minutes and included: phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), topiramate (TPM), lamotrigine (LTG), levetiracetam (LEC), ezogabine (EZG) and tiagabine (TGB).

The major findings of the study showed:

• Sodium channel blocking ASDs affect TBS-LTP differentially. (Both PHT and CBZ significantly attenuated TBS-LTP, but LTG had no significant effect on TBS-LTP in the CA1 area.)
• GABA-enhancing ASDs attenuate TBS-LTP in brain slices prepared in sucrose-based ACSF.
• Representative third generation ASDs do not effect TBS-LTP.
• Valproic acid does not affect LTP in the CA1 area but does attenuate LTP in the dentate gyrus.

The adverse effects of different ASDs on cognition can have a serious influence on a patient’s quality of life. This study shows how some ASDs can alter short and long-term plasticity. It also suggests that slice preparation technique can significantly affect the outcome of pharmacological studies of this type. These results should lead to a greater understanding of the differences in the unintended cognitive effects of ASDs and help predict how novel investigational ASDs might alter cognitive functions.

Paper reference:

West P.J., Saunders G.W., Remigio G.J. Wilcox K.S., White H.S. Antiseizure Drugs Differentially Modulate Theta-Burst Induced Long-Term Potentiation in C57BL6 Mice Epilepsia 55(2):214-223 (2014) doi: 10.1111/epi.12524