High concordance between hippocampal transcriptome of the mouse intra‐amygdala kainic acid model and human temporal lobe epilepsy

Abstract

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). Methods: 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. Results: 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 elementbinding 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. Significance: Our findings suggest the intra-amygdala kainic acid model faithfully replicates key molecular features of human drug-resistant TLE and provides potential 2796 | CONTE ET al.

Long-term in vivo application of a potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus

“…Through these pathways, cAMP regulates fundamental physiological processes such as growth, metabolism, migration, apoptosis, gene transcription, neurotransmission, and plasticity (for review, see [ 44 – 46 ]). Activation of cAMP-responsive element binding protein (CREB)-mediated gene expression could explain histological changes and seizure activity in bPAC mice as the CREB-transcriptional pathway is involved in acute and chronic phases of epilepsy [ 29 , 47 – 49 ]. A study utilizing transgenic mice with constitutively active CREB showed that chronic elevation of CREB activity in hippocampal principal neurons led to increased excitability of CA1 pyramidal neurons, significant loss of hippocampal neurons, and sporadic epileptic seizures [ 50 ], resembling what we observed in our bPAC mice.…”

In vivocharacterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus

“…Through these pathways, cAMP regulates fundamental physiological processes such as growth, metabolism, migration, apoptosis, gene transcription, neurotransmission, and plasticity (for review, see Nguyen & Woo, 2003; Cheng et al, 2008; Antoni, 2012). Altered gene expression by activation of cAMP-responsive element (CRE) could explain histological changes and seizure activity in bPAC mice as the CRE-transcriptional pathway is involved in acute and chronic phases of epilepsy (Huang et al, 1994; Hansen et al, 2014; Choi et al, 2016; Conte et al, 2020). The nuclear distribution element-like 1 (NDEL1) protein, transcribed in an activity-dependent manner by the cAMP response element-binding (CREB) protein, has been hypothesized to contribute to pathophysiological alterations of MTLE.…”

Diazepam Monotherapy or Diazepam-Ketamine Dual Therapy at Different Time Points Terminates Seizures and Reduces Mortality in a Status Epilepticus Animal Model

“…Our results demonstrate that a total dose of diazepam monotherapy terminated early SE successfully when administered less than 10 min from the beginning of SE. As time went on, gene expression of hippocampal tissue in SE model rats changed [ 20 ]. Thus, SE becomes progressively resistant to benzodiazepine anti-seizure drugs.…”