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Int. J. Mol. Sci. 2016, 17(7), 1191; doi:10.3390/ijms17071191

Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission

1
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan
2
Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 112, Taiwan
3
Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan
4
Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan
5
Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan
6
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
7
Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Masatoshi Maki
Received: 14 June 2016 / Accepted: 19 July 2016 / Published: 22 July 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [2057 KB, uploaded 22 July 2016]   |  

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. View Full-Text
Keywords: Lamotrigine; GABAergic interneuron; inhibitory postsynaptic current; voltage-gated sodium channel; hyperpolarization-activated current Lamotrigine; GABAergic interneuron; inhibitory postsynaptic current; voltage-gated sodium channel; hyperpolarization-activated current
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MDPI and ACS Style

Huang, Y.-Y.; Liu, Y.-C.; Lee, C.-T.; Lin, Y.-C.; Wang, M.-L.; Yang, Y.-P.; Chang, K.-Y.; Chiou, S.-H. Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission. Int. J. Mol. Sci. 2016, 17, 1191.

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