Abstracts

Rationale: Homeostatic synaptic plasticity has been proposed to underlie acquired epileptogenesis. This hypothesis suggests that loss of neuronal activity following brain injury will initiate epileptogenesis while replenish the lost neuronal activity by neuronal stimulation may control posttraumatic epileptogenesis. However, whether stimulating neuronal activity can prevent epileptogenesis has not been directly tested. Methods: In the partially isolated neocortex model of posttraumatic epileptogenesis (undercut), we made patch clamp recording from cortical layer V pyramidal neurons to determine changes in neuronal firing and synaptic transmission after brain injury. We further prepared undercut lesion in Thy1-channelrhodopsin-2 (ChR2) transgenic mice that express ChR2 in cortical layer V pyramidal neurons, and applied optogenetic stimulation for 7 days in vivo. Field potential recordings from cortical slices were made to evaluate potential change in epileptogenesis. Results: We found that in the undercut model, spontaneous firing of action potentials in cortical layer V pyramidal neurons was significantly reduced at 1 and 7 days after injury. The frequencies of both spontaneous excitatory and inhibitory synaptic currents (sEPSCs and sIPSCs) were also significantly depressed, but without significant changes in the amplitudes of these events. Chronic optogenetic stimulation resulted in attenuation of posttraumatic epileptogenesis, as indicated by decreases in the percentages of slices and mice in which epileptiform activity could be evoked. Furthermore, the frequencies of both sEPSCs and sIPSCs in neurons after optogenetic stimulation were significantly lower that of the undercut mice. Conclusions: The results support that homeostatic plasticity plays a role in the posttraumatic epileptogenesis in the undercut model and that stimulating activity of cortical excitatory neurons has prophylactic effect on posttraumatic epileptogenesis.