The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Abstract

BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair

“…on the activation other intrinsic or synaptic channels in a given neuron. Indeed, for example, depending on their synaptic and intrinsic context, sodium 84 , A-type potassium 33 , 85 , SK 37 , 86 and HCN channels 87 – 90 can contribute to a suppression or an enhancement of neuronal spiking. Therefore, predicting how a specific channel alteration affects neuronal excitability will require detailed models and experimental analyses of ion channel degeneracy.…”

Understanding Lamotrigine’s Role in the CNS and Possible Future Evolution

“…LTG has been shown to modulate HCN channels in a number of ways [ 52 ]. First, it can directly block the HCN channels, thereby reducing the pacemaker current and slowing down the firing rate of neurons [ 53 ]. Second, it can increase the sensitivity of HCN channels to cyclic nucleotides, which can also reduce neuronal excitability [ 51 , 53 ].…”

“…First, it can directly block the HCN channels, thereby reducing the pacemaker current and slowing down the firing rate of neurons [ 53 ]. Second, it can increase the sensitivity of HCN channels to cyclic nucleotides, which can also reduce neuronal excitability [ 51 , 53 ]. The modulation of HCN channels by lamotrigine may impact disease outcomes and potential side effects.…”

“…The modulation of HCN channels by lamotrigine may impact disease outcomes and potential side effects. For example, the reduction of neuronal excitability by lamotrigine may be beneficial in the treatment of epilepsy and bipolar disorder, where excessive neuronal activity can lead to seizures and mood instability [ 53 ]. Still, on the other hand, it can inhibit pacemaker currents in the heart.…”

“…Lamotrigine modulates HCN channels and has been shown to affect intracellular calcium signaling by inhibiting the release of calcium ions from intracellular stores and reducing the influx of calcium ions through voltage-gated calcium channels (VGCCs). The reduction of calcium influx can influence the calcium-dependent signaling pathways that are activated by HCN channels [ 53 , 55 ]. Further research is needed to fully understand the mechanisms underlying the interaction between HCN channels, calcium ions, and lamotrigine, and to develop new therapies for neurological and psychiatric disorders that target these pathways.…”