Increased excitation-inhibition balance of the cortex in the mouse model of the focal malformation of cortical development

Abstract

A typical symptom of epilepsy, a type of neurological disorder, includes a seizure caused by the sudden and disorderly over-excitement of neurons. This symptom can be controlled by medication in ~80 % of patients but not in ~20% of the intractable cases due to the gap between the target of the anticonvulsants and the causes. In the current study, we explored the abnormality of the circuits in the mouse model of focal malformation of cortical development (FMCD), which shows the intractable seizure. We found that the FMCD mouse model shows an increased intrinsic excitability not only in the neurons with somatic mutation, but also in neighboring neurons throughout cortical layers. Pyramidal neurons in the cortex with FMCD showed increased excitability by increased input resistance and depolarized resting membrane potential. In addition, a significant increase in the HCN-dependent rebounding current was observed in the mutant neurons. Consistently, we observed a dramatic decrease in the rheobase and increase in the firing frequency in response to the same amount of current injection. Furthermore, we found that the frequency of spontaneous inhibitory postsynaptic current (sIPSC) was significantly reduced. The reduction in the frequency of sIPSC can be attributed to reduction in (1) the excitability, (2) the release probability, or the number of inhibitory neurons of the cortical circuit. To distinguish these possibilities, we are currently analyzing the pathological features of the inhibitory neurons in FMCD mouse model.