Changes in Metabotropic Glutamate Receptor Gene Expression in Rat Brain in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy.

Anna A Kovalenko,Olga E Zubareva,Alexandra V Dyomina,Alexander P Schwarz,Maria V Zakharova,Aleksey V Zaitsev

doi:10.3390/ijms23052752

Abstract

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. This study aimed to analyze the changes in gene expression of mGluR subtypes (1–5, 7, 8) in various rat brain regions in the latent and chronic phases of a lithium–pilocarpine model of epilepsy. For this study, multiplex test systems were selected and optimized to analyze mGluR gene expression using RT-qPCR. Region- and phase-specific changes in expression were revealed. During the latent phase, mGluR5 mRNA levels were increased in the dorsal and ventral hippocampus, and expression of group III genes was decreased in the hippocampus and temporal cortex, which could contribute to epileptogenesis. Most of the changes in expression detected in the latent stage were absent in the chronic stage, but mGluR8 mRNA production remained reduced in the hippocampus. Moreover, we found that gene expression of group II mGluRs was altered only in the chronic phase. The study deepened our understanding of the mechanisms of epileptogenesis and suggested that agonists of group III mGluRs are the most promising targets for preventing epilepsy.

Highlights

Epilepsy is a chronic neurological disorder that affects millions of people [1]
The lithium–pilocarpine model used in our study is the most relevant model of temporal lobe epilepsy (TLE) [16,17]
The lithium–pilocarpine model was used in our study because it most closely reproduces the pathological changes occurring in patients with TLE

Summary

Introduction

Epilepsy is a chronic neurological disorder that affects millions of people [1]. Standard antiseizure medications fail to control seizures in about a fifth to a third of patients [2].Since up to 40% of cases are an acquired form of epilepsy, prevention of epilepsy in patients at risk is a primary unmet medical need [3]. Epilepsy is a chronic neurological disorder that affects millions of people [1]. Standard antiseizure medications fail to control seizures in about a fifth to a third of patients [2]. Since up to 40% of cases are an acquired form of epilepsy, prevention of epilepsy in patients at risk is a primary unmet medical need [3]. The difficulties in preventing epilepsy are due to the lack of knowledge of the pathogenetic mechanisms of its development. An imbalance between excitatory and inhibitory neurotransmission is one of the critical mechanisms of epileptogenesis [4,5]. Metabotropic glutamate receptors (mGluRs) modulate excitatory and inhibitory synaptic transmission and plasticity [6,7]. MGluRs are essential in maintaining the excitation/inhibition balance [8]; they have been shown to be directly involved in epileptogenesis [9]

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