TMT-based proteomics profile reveals changes of the entorhinal cortex in a kainic acid model of epilepsy in mice

Abstract

Experimental modeling and clinical neuroimaging of patients has shown that certain seizures are capable of causing neuronal death. Research into cell death after seizures has identified the induction of the molecular machinery of apoptosis. Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults, which is characterized by substantial pathological abnormalities in the temporal lobe, including the hippocampus and entorhinal cortex (EC). Although decades of studies have revealed numerous molecular abnormalities in the hippocampus that are linked to TLE, the biochemical mechanisms associated with TLE in EC remain unclear. In this study, we explored these early phenotypical alterations in the EC 5 days after mice were given a systemic injection of kainic acid (KA) to induce status epilepticus (KA-SE). we used the Tandem Mass Tag (TMT) combined with LC-MS/MS approach to identify distinct proteins in the EC in a mouse model of KA-SE model. According to the findings, 355 differentially abundant proteins including 199 upregulated and 156 downregulated differentially abundant proteins were discovered. The first-ranked biological process according to Gene Ontology (GO) analysis was "negative control of extrinsic apoptotic signaling". "Apoptosis" was the most significantly enriched Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway. Compared with those in control mice, BCL2L1, NTRK2 and MAPK10 abundance levels were reduced in KA mice. MAPK10 and NTRK2 act as upstream regulators to regulate BCL2L1, and BCL2L1 Inhibits cell death by blocking the voltage- dependent anion channel (VDAC) and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. However, ITPR1 was increased at the mRNA and protein levels in KA mice. Furthermore, there was no significant difference in ACTB, TUBA1A and TUBA4A levels between the two groups. Our results offer clues to help identify biomarkers for the development of pharmacological therapies targeted at epilepsy.

Keywords: Apoptosis; Entorhinal cortex; Kainic acid; Proteomic analysis; Status epilepticus; Temporal lobe epilepsy.