Investigation Into The Function Of Cox-2 In A Mouse Model Of Lgi1 Deficiency Induced Epilepsy

Autosomal dominant lateral temporal epilepsy(ADLTE)is an inherited epilepsy syndrome caused by mutations in leucine-rich glioma inactivated gene 1(Lgi1).It has been shown that glutamatergic transmission is altered in Lgil mutant mice and seizures can be reduced by restoring Lgi1 function.Yet,the underlying mechanism for ADLTE is unclear.Here,I examined the intrinsic excitability of pyramidal neurons in the temporal lobe cortex on slices from Lgil knockout mice and wild type littermatters by patch clamp whole cell recordings.I found that the expression and current of voltage--gated potassium channel subfamily A(Kvl)were downregulated.Using various biochemical tests,I also found that cytosolic phospholipase A2(CPLA2)--cyclooxygenase 2(Cox-2)signaling was enhanced in brain tissue as well as cultured neuron from Lgi1 knockout mice.Pharmacological or genetic inhibition of Cox-2 effectively restored dysregulated Kv1.2 and reduced intrinsic excitability of pyramidal neurons.Interestingly,in vivo injection with celecoxib,a Food and Drug Administration-approved nonsteroidal anti-inflammatory drug ameliorated neuronal excitability through Kvl.2,reduced seizure susceptibility and prolonged life span of Lgil knockout mice.Taken together,I propose that the abnormal activation of Cox-2 signaling can cause the seizures in Lgi1 knockout mice.Downregulation the signaling pathway can rescue the hyperexcitability of pyramidal neuron through Kv1.2,thus ameliorated seizure susceptibility of Lgi1 knockout mice.Therefore,I propose that Cox-2 is a therapeutic target to suppress seizures in ADLTE patients.