High concordance between hippocampal transcriptome of the mouse intra‐amygdala kainic acid model and human temporal lobe epilepsy
Pharmacoresistance and the lack of disease‐modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant‐induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra‐amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug‐resistant temporal lobe epilepsy (TLE).
Status epilepticus was induced via intra‐amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time‐points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug‐resistant TLE.
Intra‐amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3‐fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element‐binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra‐amygdala kainic acid model.
Our findings suggest the intra‐amygdala kainic acid model faithfully replicates key molecular features of human drug‐resistant TLE and provides potential rational target approaches for disease‐modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.Read More...