Inhibition of the small GTPase Cdc42 in regulation of epileptic-seizure in rats

• A high expression of Cdc42 was found in pilocarpine epileptic rat models after kindling compared with normal ones.
• Blocking Cdc42 prolonged the latency of seizure onset and reduced seizure severity in the epileptic rats.
• Blocking Cdc42 down-regulated the spontaneous action potential frequency.
• Blocking Cdc42 increased the miniature and the evoked inhibitory postsynaptic currents in the epileptic neurons.
• Blocking Cdc42 has no impact on miniature excitatory postsynaptic currents in the epileptic neurons.

Altered expression of neuronal cytoskeletal proteins are known to play an important role in hyper-excitability of neurons in patients and animal models of epilepsy. Our previous work showed that cell division cycle 42 GTP-binding protein (Cdc42), a small GTPase of the Rho-subfamily, is significantly increased in the brain tissue of patients with temporal lobe epilepsy (TLE) and in the brain tissues of the epileptic model of rats. However, whether inhibition of Cdc42 can modify epileptic seizures has not been investigated. In this study, using a pilocarpine-induced epileptic model, we found that pretreatment with ML141, a specific inhibitor of Cdc42, reduces seizure severity. Whole-cell patch-clamp recording on CA1 pyramidal neurons in hippocampal slices from pilocarpine-induced epileptic model demonstrated that ML141 significantly inhibits the frequency of action potentials (APs), increases the amplitude and frequency of miniature inhibitory postsynaptic currents (mIPSCs), and increases the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). However, ML141 did not have an impact on the miniature excitatory postsynaptic currents (mEPSCs). Our results are the first to indicate that Cdc42 plays an important role in the onset and progression of epileptic-seizures by regulating synaptic inhibition.