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.
Highlights
Lamotrigine (LTG), a broad-spectrum antiepileptic drug (AED), is effective and well tolerated in the treatment of partial and generalized seizures among adults, women in pregnancy and children [1,2,3]
LTG, which is considered as an Ih enhancer, is shown to facilitate spontaneous inhibitory postsynaptic currents (IPSCs) in cornus ammonis region 1 (CA1) pyramidal cells (PCs) [13,14]
LTG is known as a sodium channel blocker, which can inhibit IN excitability and, suppress synaptic outputs
Summary
Lamotrigine (LTG), a broad-spectrum antiepileptic drug (AED), is effective and well tolerated in the treatment of partial and generalized seizures among adults, women in pregnancy and children [1,2,3]. LTG is used for other non-epileptic conditions, like bipolar disorder [4,5,6]. It acts on multiple molecular targets in the central nervous system, LTG mainly serves as a voltage-gated Na+ (Nav) channel blocker [7,8,9,10]; it can suppress the neuronal excitability and block neurotransmitter release. The enhanced GABAergic transmission correlates with the increased spontaneous firing rate of a specific population of CA1 interneurons (INs) possibly via potentiation of hyperpolarization-activated cation channels (Ih or HCN channels) by LTG [13,14]. Ih channels are highly expressed in the majority of the dendrite-targeting CA1 INs [15,16,17]
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