Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible L eucine-rich glioma-inactivated 1 (Lgi1)-mutant rats

Masato Kinboshi; Saki Shimizu; Kentaro Tokudome; Tomoji Mashimo; Tadao Serikawa; Hidefumi Ito; Ryosuke Takahashi; Akio Ikeda; Yukihiro Ohno

doi:10.1016/j.heliyon.2023.e17984

Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible L eucine-rich glioma-inactivated 1 (Lgi1)-mutant rats

Heliyon. 2023 Jul 5;9(7):e17984. doi: 10.1016/j.heliyon.2023.e17984. eCollection 2023 Jul.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan.
² Department of Neurology, Wakayama Medical University, Wakayama, 641-8509, Japan.
³ Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
⁴ Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
⁵ Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.

Abstract

Leucine-rich glioma-inactivated 1 (LGI1) was identified as a causative gene of autosomal dominant lateral temporal lobe epilepsy. We previously reported that Lgi1-mutant rats carrying a missense mutation (L385R) showed audiogenic seizure-susceptibility. To explore the pathophysiological mechanisms underlying Lgi1-related epilepsy, we evaluated changes in glutamate and GABA release in Lgi1-mutant rats. Acoustic priming (AP) for audiogenic seizure-susceptibility was performed by applying intense sound stimulation (130 dB, 10 kHz, 5 min) on postnatal day 16. Extracellular glutamate and GABA levels in the hippocampus CA1 region were evaluated at 8 weeks of age, using in vivo microdialysis techniques. Under naïve conditions without AP, glutamate and GABA release evoked by high-K⁺ depolarization was more prominent in Lgi1-mutant than in wild-type (WT) rats. The AP treatment on day 16 significantly increased basal glutamate levels and depolarization-induced glutamate release both in Lgi1-mutant and WT rats, yielding greater depolarization-induced glutamate release in Lgi1-mutant rats. On the other hand, the AP treatment enhanced depolarization-induced GABA release only in WT rats, and not in Lgi1-mutant rats, illustrating reduced GABAergic neurotransmission in primed Lgi1-mutant rats. The present results suggest that enhanced glutamatergic and reduced GABAergic neurotransmission are involved in the audiogenic seizure-susceptibility associated with Lgi1-mutation.

Keywords: ADLTE; Audiogenic seizure; Epilepsy; GABA; Glutamate; Lgi1.