Activation of long-term synaptic plasticity causes suppression of epileptiform activity in rat hippocampal slices

Abstract

Electrical stimulation of cerebral targets for the treatment of epilepsy is an area under active investigation. Recent studies have shown that chronic stimulation of the subthalamic nucleus, fornix, or hippocampus may be effective in attenuating seizure frequency in animal models and in patients with intractable epilepsy. However, many questions exist, such as what are the specific electrical parameters, target sites, and mechanisms, etc., which should be investigated in animal studies before considering the routine use of chronic stimulation in epileptic patients. It is also important to understand what happens to neural activity during repetitive pulse stimulation as well as after stimulation. To this end, we hypothesized: (1) activation of synaptic plasticity suppresses epileptiform activity and (2) low frequency stimulation is an effective stimulation protocol for reducing seizure intensity and frequency. We used rat hippocampal brain slices to study how electrical stimulation affects spontaneous and evoked epileptiform activity. Further, we compared low (1 Hz) versus high (100 Hz) frequency stimulation in the same preparation. We found that orthodromic stimulation of the Schaffer collaterals for 10 min reduces the amplitude of normal responses and diminishes epileptiform activity. The onset of suppression by 1 Hz stimulation was gradual, but persistent, whereas the onset of suppression by 100 Hz was rapid; however, the effects of 100 Hz stimulation were transient. Finally, the NMDA antagonist, AP5 reversed the antiepileptic effects achieved by 1 Hz stimulation. Collectively, these data suggest that using different stimulation parameters prolonged electrical stimulation in the hippocampus may be effective in reducing seizure frequency in patients with epilepsy and that suppression by low frequency stimulation may be mediated by long-term depression (LTD).