Evaluation of seizure foci and genes in the Lgi1 mutant rat

Abstract

Mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene have been identified in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We previously reported that Lgi1 mutant rats, carrying a missense mutation (L385R) generated by gene-driven N-ethyl-N-nitrosourea (ENU) mutagenesis, showed generalized tonic-clonic seizures (GTCS) in response to acoustic stimuli. In the present study, we assessed clinically relevant features of Lgi1 heterozygous mutant rats (Lgi1(L385R/+)) as an animal model of ADLTE. First, to explore the focus of the audiogenic seizures, we performed electroencephalography (EEG) and brain Fos immunohistochemistry in Lgi1(L385R/+) and wild type rats. EEG showed unique seizure patterns (e.g., bilateral rhythmic spikes) in Lgi1(L385R/+) rats with GTCS. An elevated level of Fos expression indicated greater neural excitability to acoustic stimuli in Lgi1(L385R/+) rats, especially in the temporal lobe, thalamus and subthalamic nucleus. Finally, microarray analysis revealed a number of differentially expressed genes that may be involved in epilepsy. These results suggest that Lgi1(L385R/+) rats are useful as an animal model of human ADLTE.

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

“…Thus, our results suggest that the elevation of astrocytic Kir4.1 expression in limbic regions by the antiepileptic drugs contributes to their antiepileptic actions. Indeed, in our preliminary studies using audiogenic seizure susceptible Lgi1 L 385 R mutant rats (Baulac et al, 2012 ; Fumoto et al, 2014 ), repeated treatment with valproate alleviated epileptogenesis (development of seizure susceptibility) of the Lgi1 L 385 R mutant rats which exhibited down-regulation of astrocytic Kir4.1 expression (Kinboshi et al, 2017b ).…”

A Missense Mutation of the Gene Encoding Synaptic Vesicle Glycoprotein 2A (SV2A) Confers Seizure Susceptibility by Disrupting Amygdalar Synaptic GABA Release

“…Fos protein is the immediate early gene product and is widely used as a cellular marker of neural excitation. Specifically, brain mapping analysis of Fos expression is useful to identify brain regions related to disease conditions (e.g., epilepsy, emotional disorders and cognitive impairments) or responses to various pathophysiological and pharmacological stimuli (e.g., pain, body temperature, stress, and drug treatments; Morgan and Curran, 1989 ; Herrera and Robertson, 1996 ; Ohno et al, 2009b , 2011 , 2012a , 2015 ; Mukai et al, 2013 ; Fumoto et al, 2014 ; Iha et al, 2016 ). In the present study, we treated animals with the seizure threshold dose (30 mg/kg, i.p.)…”

Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats

“…Topographical mapping analysis for the changes in Kir4.1 and GFAP expression was performed by counting the number of Kir4.1-IR-positive and GFAP-IR-positive cells stained by the avidin-biotin complex (ABC) method. Nineteen brain regions were analyzed, including the cerebral cortex, hippocampus, amygdala, thalamus, and hypothalamus, which were reported to be activated with audiogenic seizures in Lgi1 mutant rats [28] (Figure 2B). Kir4.1-IR was mostly expressed in stellate-shaped cells, and there was no morphological difference in Kir4.1-IR or GFAP-IR positive cells between WT and Lgi1 mutant rats (Figure 2C).…”

“…We previously developed a novel rat model of Lgi1-related seizures that carries a missense mutation (L385R) of the Lgi1 gene [27]. The Lgi1 mutant rats showed audiogenic seizure susceptibility, resembling the clinical features of ADLTE [27,28]. In the present study, we evaluated the Kir4.1 expressional changes in astrocytes during the development of audiogenic epilepsy in Lgi1 mutant rats to clarify the potential involvement of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis.…”