Antiseizure drugs differentially modulate θ-burst induced long-term potentiation in C57BL/6 mice.
OBJECTIVE
Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. In addition, the actions of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the National Institute of Neurological Disorders and Stroke (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. Although the effects of some ASDs on LTP have been examined, none of these studies employed physiologically relevant induction stimuli such as theta-burst stimulation (TBS). To systematically evaluate the effects of multiple ASDs in the same preparation using physiologically relevant stimulation protocols, we examined the effects of a broad panel of existing ASDs on TBS-induced LTP in area CA1 of in vitro brain slices, prepared in either normal or sucrose-based artificial cerebrospinal fluid (ACSF), from C57BL/6 mice.


METHODS
Coronal brain slices containing the dorsal hippocampus were made using either standard or sucrose-based ACSF. 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 that served as controls. Field excitatory postsynaptic potentials (fEPSPs) were recorded, and all ASDs were applied to slices by bath perfusion for 20 min prior to the induction stimulus. LTP was induced by TBS or by high-frequency stimulation (HFS). The following ASDs were examined: 100 μM phenobarbital (PB), 80 μM phenytoin (PHT), 50 μM carbamazepine (CBZ), 600 μM valproate (VPA), 60 μM topiramate (TPM), 60 μM lamotrigine (LTG), 100 μM levetiracetam (LEV), 10 μM ezogabine (EZG), and 30 μM tiagabine (TGB).


RESULTS
Among voltage-gated sodium channel inhibitors, CBZ significantly attenuated TBS-induced LTP, PHT attenuated both TBS-induced LTP and post-tetanic potentiation (PTP), and LTG failed to affect LTP but did attenuate PTP. ASDs that modulate γ-aminobutyric acid (GABA)ergic synaptic transmission, such as PB and TGB, significantly attenuated LTP in brain slices prepared in sucrose-based ACSF but not standard ACSF. Third generation ASDs, such as LEV and TPM, did not affect LTP in ACSF- or sucrose-prepared brain slices. Although EZG failed to affect LTP, it did significantly attenuate PTP under both slicing conditions. VPA failed to affect LTP in area CA1, both in C57BL/6 mice and Sprague-Dawley rats, using TBS or HFS. However, VPA did attenuate TBS-induced LTP in the dentate gyrus (DG).


CONCLUSIONS
The results of experiments describe herein provide a comprehensive summary of the effects of many commonly used ASDs on short- and long-term synaptic plasticity while, for the first time, using physiologically relevant LTP induction protocols and slice preparations from mice. Furthermore, methodologic variables, such as brain slice preparation protocols, were explored. These results provide comparative knowledge of ASD effects on synaptic plasticity in the mouse hippocampus and may ultimately contribute to an understanding of the differences in the cognitive side effect profiles of ASDs and the prediction of cognitive dysfunction associated with novel investigational ASDs.
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A; Interdepartmental Neuroscience Program, University of Utah, Salt Lake City, Utah, U.S.A.
Peter J
PJ
West
Gerald W
GW
Saunders
Gregory J
GJ
Remigio
Karen S
KS
Wilcox
H Steve
HS
White
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013826:Theta Rhythm / Q000187:drug effects / Q000502:physiology*
D000927:Anticonvulsants
Antiepileptic drugs; Cognitive testing; Learning and memory; Post tetanic potentiation; Sucrose; Synaptic plasticity