Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible Leucine-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
Affiliations
Masato Kinboshi
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan; Department of Neurology, Wakayama Medical University, Wakayama, 641-8509, Japan; Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan
Saki Shimizu
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan
Kentaro Tokudome
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan
Tomoji Mashimo
Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan
Tadao Serikawa
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan
Hidefumi Ito
Department of Neurology, Wakayama Medical University, Wakayama, 641-8509, Japan
Ryosuke Takahashi
Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan
Akio Ikeda
Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan
Yukihiro Ohno
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan; Corresponding author. Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094 TEL, Japan.
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.
