title: Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission.
abstract: Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Nav) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Nav channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (Ih) enhancement. In summary, LTG has no effect on augmenting Ih in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Nav channel inhibition and the suppression of global neuronal network activity.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan. huang_yuyin@yahoo.com.tw.|Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 112, Taiwan. huang_yuyin@yahoo.com.tw.
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 112, Taiwan. rainnyhunter@gmail.com.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan. tsohchi@hotmail.com.
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan. g39601013@gmail.com.
authors.forename: Yen-Chu
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan. monglien@gmail.com.
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan. molly0103@gmail.com.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. molly0103@gmail.com.|Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan. molly0103@gmail.com.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112, Taiwan. kychang@vghtpe.gov.tw.
authors.forename: Kaung-Yi
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.|Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D000077213:Lamotrigine; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D000077213:Lamotrigine
keywords: GABAergic interneuron; Lamotrigine; hyperpolarization-activated current; inhibitory postsynaptic current; voltage-gated sodium channel