Antiseizure drugs differentially modulate theta‐burst induced long‐term potentiation in C 57 BL /6 mice

Summary Objective Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. In addition, the actions of some antiseizure drugs ( ASD s) 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 ASD s 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 ASD s 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 ASD s in the same preparation using physiologically relevant stimulation protocols, we examined the effects of a broad panel of existing ASD s on TBS ‐induced LTP in area CA 1 of in vitro brain slices, prepared in either normal or sucrose‐based artificial cerebrospinal fluid ( ACSF ), from C 57 BL /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 S cientifica S licemaster high throughput recording system. Slices exposed to ASD s were paired with slices from the opposite hemisphere that served as controls. Field excitatory postsynaptic potentials (f EPSP s) were recorded, and all ASD s 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 ASD s 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 . ASD s 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 ASD s, 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 CA 1, both in C 57 BL /6 mice and Sprague‐Dawley rats, using TBS or HFS . However, VPA did attenuate TBS ‐induced LTP in the dentate gyrus ( DG ). Significance The results of experiments describe herein provide a comprehensive summary of the effects of many commonly used ASD s 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 ASD s.