Levetiracetam Induction Of Theta Frequency Oscillations In Rodent Hippocampus In Vitro

BackgroundLevetiracetam(LEV),a new type of anti epileptic drug,has been recently demonstrated to improve the cognitive function.Hippocampal theta rhythm(4-12Hz)is associated with a variety of cognitively related behaviors,such as exploration,locomotion and spatial memory in both humans and animal models.Whether LEV affects theta oscillation has not yet been reported.ObjectiveThis study aimed to examine the role of the LEV in the generation of theta oscillations in vitro and the effect of LEV on the sniffing behavior of rats related to hippocampal theta oscillations.MethodElectrophysiological studies were performed on hippocampal CA3 area slices to measure theta oscillation induced by LEV,and further examined the effect of glutamate receptor antagonists or GABAa receptor antagonist or Ach receptor antagonist or taurine on LEV-induced theta oscillation,respectively.Behavioral methods(object-location task)test the sniffing behavior of rats related to hippocampal theta oscillations.ResultWe investigated the effects of LEV on the theta rhythm in the rat and found that LEV increased the power of theta oscillation in a dose-dependent manner.The increase in theta power can be blocked by GABAA receptor or NMDA receptor antagonists but not by AMPA receptor antagonist,indicating the involvement of GABAa receptor and NMDA receptor in the induction of theta activity.Interestingly,LEV enhancement of theta power can be also blocked by taurine,indicating that LEV induction of theta maybe related to the indirect boosting of GABA action via reduction of extrasynaptic GABAA receptor activation.Furthermore,the increased theta power can be partially reduced by muscarinic Ach receptor antagonist atropine but not by nicotinic Ach receptor antagonists,suggesting that muscarinic Ach receptor activation provides excitatory input into local network responsible for LEV induction of theta.LEV increased exploration time in object location test task in acquisition phase,suggesting LEV-induced theta oscillations are associated with sniffing task.ConclusionLEV is able to induce persistent theta frequency oscillation activity in the CA3 area of the hippocampal slices,which are mediated by NMDA receptors and GABAA receptors,partially mediated by mACh receptor.Taurine is also involved in the induction of theta oscillation by LEV.LEV can increase the sniffing time in the acquisition phase,suggesting that it maybe related to the enhancement effect of LEV on theta oscillation.LEV may especially benefit for the treatment of the neuronal disorders with impaired theta oscillation and cognitive function.