HCN channels in behavior and neurological disease: Too hyper or not active enough?

Lewis, Alan S.; Chetkovich, Dane M.

doi:10.1016/j.mcn.2010.11.007

Cited by 76 publications

(69 citation statements)

References 108 publications

(181 reference statements)

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“…The I h current, coded for by HCN channels, is normally activated at resting voltage levels (Maccaferri et al, 1993) and can therefore contribute importantly to control of excitability and plasticity phenomena (Robinson and Siegelbaum, 2003;Lewis and Chetkovich, 2011). HCN channels affect rhythmic activity in firing neurons and their expression in dendrites represents an important factor modulating integrative properties of the neuron (Magee, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Widely expressed in neurons, HCN channels have important functions such as the modulation of excitability and rhythmicity, signal integration, and plasticity (I h current) (Pape, 1996;Robinson and Siegelbaum, 2003;Biel et al, 2009). Because of their role in neuronal excitability, defective HCN1/HCN2 channels, the HCN isoforms expressed in distal dendrites of pyramidal cells in the hippocampus and neocortex (Notomi and Shigemoto, 2004), are considered potential contributors to pathological firing in specific forms of epilepsy (Bender and Baram, 2008;Dubé et al, 2009;Dyhrfjeld-Johnsen et al, 2009;Reid et al, 2009;Lewis and Chetkovich, 2011). Evidence supporting a link between functional alteration of HCN channels and epileptogenesis has resulted typically from analysis of Hcn1 and Hcn2 knock-out mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

DiFrancesco¹,

Barbuti²,

Milanesi³

et al. 2011

J. Neurosci.

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The hyperpolarization-activated I h current, coded for by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, controls synaptic integration and intrinsic excitability in many brain areas. Because of their role in pacemaker function, defective HCN channels are natural candidates for contributing to epileptogenesis. Indeed, I h is pathologically altered after experimentally induced seizures, and several independent data indicate a link between dysfunctional HCN channels and different forms of epilepsy. However, direct evidence for functional changes of defective HCN channels correlating with the disease in human patients is still elusive.By screening families with epilepsy for mutations in Hcn1 and Hcn2 genes, we found a recessive loss-of-function point mutation in the gene coding for the HCN2 channel in a patient with sporadic idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the mutation.The mutation (E515K) is located in the C-linker, a region known to affect channel gating. Functional analysis revealed that homomeric mutant, but not heteromeric wild-type/mutant channels, have a strongly inhibited function caused by a large negative shift of activation range and slowed activation kinetics, effectively abolishing the HCN2 contribution to activity. After transfection into acutely isolated newborn rat cortical neurons, homomeric mutant, but not heteromeric wild type/mutant channels, lowered the threshold of action potential firing and strongly increased cell excitability and firing frequency when compared with wild-type channels. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

DiFrancesco¹,

Barbuti²,

Milanesi³

et al. 2011

J. Neurosci.

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“…In normal brain, the HCN1 channel mediates the I(h) current, and keeps in check the intrinsic excitability of pyramidal cell dendrites in the entorhinal cortex and hippocampus (Lewis and Chetkovich, 2011). Accordingly, HCN1 null mice exhibit increased dendritic excitability and susceptibility to seizures in an experimental model of temporal lobe epilepsy (Huang et al, 2009).…”

Section: Transcriptional Regulation By Rest In Epilepsymentioning

confidence: 99%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.

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“…The HCN family of channels is involved in numerous physiological functions in the central nervous system and heart where they are responsible for the I f current in the sinoatrial node (SAN). HCN channels have been shown to be involved in the pathophysiology of neurological disorders, including epilepsy (reviewed by Lewis and Chetkovich 7 ) and chronic pain, 8 as well as in retinal physiology 9 (see Table 1 for a summary of HCN functions in extracardiac pathophysiology). HCN channels have also emerged as interesting targets for the development of drugs that lower HR.…”

mentioning

confidence: 99%