Abstracts

Rationale: Homeostatic activity regulation has been proposed to underlie acquired epileptogenesis. This hypothesis suggests that initial loss of neuronal activity following brain injury contributes to epileptogenesis while enhancing neuronal excitatory activity may prevent it. However, the neurophysiological mechanism of such regulation is not clear and whether stimulating activity will prevent epileptogenesis has not been directly tested.Methods: In a partially isolated neocortex model (undercut) of posttraumatic epileptogenesis in mice, we made patch clamp recordings from cortical layer V pyramidal neurons at different times after injury. To test the effect of cortical stimulation on preventing epileptogenesis, we enhanced cortical excitatory activity by applying optogenetic stimulation to the undercut cortex in channelrhodopsin-2 expressing transgenic mice for 7 days or implanting Elvax that chronically released GABAA receptor antagonist bicuculline on cortical surface. The effects were evaluated with field potential recording from cortical slices and pentylenetetrazol (PTZ) test in vivo.Results: We found that spontaneous action potential firing in cortical pyramidal neurons was significantly reduced at both 1 and 7 days after injury. The frequencies of both spontaneous excitatory and inhibitory synaptic currents (sEPSCs and sIPSCs) were significantly depressed but the amplitudes remained unchanged. Both optogenetic stimulation and bicuculline-Elvax application resulted in an increased seizure threshold as indicated by a higher PTZ dosage required for seizure induction and a longer latency period. After optogenetic stimulation, the percentages of slices in which epileptiform activity could be evoked became lower, and the frequencies of both sEPSCs and sIPSCs in cortical pyramidal neurons were lower than neurons without stimulation.Conclusions: We conclude that homeostatic plasticity plays a role in the posttraumatic epileptogenesis and that stimulating activity of cortical excitatory neurons has prophylactic effect on posttraumatic epileptogenesis.