Functional variants in  HCN 4  and  CACNA 1H  may contribute to genetic generalized epilepsy

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Summary

Objective

Genetic generalized epilepsy ( GGE) encompasses seizure disorders characterized by spike‐and‐wave discharges ( SWD) originating within thalamo‐cortical circuits. Hyperpolarization‐activated ( HCN) and T‐type Ca ²⁺ channels are key modulators of rhythmic activity in these brain regions. Here, we screened HCN4 and CACNA1H genes for potentially contributory variants and provide their functional analysis.

Methods

Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE, and the results confirmed in 230 ethnically matching controls. Selected variants in CACNA1H and HCN4 were functionally assessed in tsA201 cells and Xenopus laevis oocytes, respectively.

Results

We discovered a novel CACNA1H (p.G1158S) variant in two affected members of a single family. One of them also carried an HCN4 (p.P1117L) variant inherited from the unaffected mother. In a separate family, an HCN4 variant (p.E153G) was identified in one of several affected members. Voltage‐clamp analysis of CACNA1H (p.G1158S) revealed a small but significant gain‐of‐function, including increased current density and a depolarizing shift of steady‐state inactivation. HCN4 p.P1117L and p.G153E both caused a hyperpolarizing shift in activation and reduced current amplitudes, resulting in a loss‐of‐function.

Significance

Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE.

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Most cited references 43

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Hyperpolarization-activated cation channels: from genes to function.

Martin Biel, Christian Wahl-Schott, Stylianos Michalakis … (2009)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as I(h) (or I(f) or I(q)). I(h) has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that I(h) is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of I(h) are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

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On the cellular and network bases of epileptic seizures.

D A McCormick, D Contreras (2001)

The highly interconnected networks of the mammalian forebrain can generate a wide variety of synchronized activities, including those underlying epileptic seizures, which often appear as a transformation of otherwise normal brain rhythms. The cerebral cortex and hippocampus are particularly prone to the generation of the large, synchronized bursts of activity underlying many forms of seizures owing to strong recurrent excitatory connections, the presence of intrinsically burst-generating neurons, ephaptic interactions among closely spaced neurons, and synaptic plasticity. The simplest form of epileptiform activity in these structures is the interictal spike, a synchronized burst of action potentials generated by recurrent excitation, followed by a period of hyperpolarization, in a localized pool of pyramidal neurons. Seizures can also be generated in response to a loss of balance between excitatory and inhibitory influences and can take the form of either tonic depolarizations or repetitive, rhythmic burst discharges, either as clonic or spike-wave activity, again mediated both by intrinsic membrane properties and synaptic interactions. The interaction of the cerebral cortex and the thalamus, in conjunction with intrathalamic communication, can also generate spike waves similar to those occurring during human absence seizure discharges. Although epileptic syndromes and their causes are diverse, the cellular mechanisms of seizure generation appear to fall into only two categories: rhythmic or tonic "runaway" excitation or the synchronized and rhythmic interplay between excitatory and inhibitory neurons and membrane conductances.

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Closed-loop optogenetic control of thalamus as a new tool to interrupt seizures after cortical injury

Jeanne Paz, Thomas J. Davidson, Eric Frechette … (2012)

Cerebrocortical injuries, such as stroke, are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, yet mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. Here we report in rats the first evidence that the thalamus – a structure remote from but connected to the injured cortex – is required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex undergo changes in HCN channel expression and become hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy demonstrates that reducing their activity in real-time is sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, since it spares cortical function between seizures, in contrast to existing treatments such as surgical lesioning or drugs.

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Author and article information

Contributors

Snezana Maljevic: snezana.maljevic@florey.edu.au

Journal

Journal ID (nlm-ta): Epilepsia Open

Journal ID (iso-abbrev): Epilepsia Open

Journal ID (doi): 10.1002/(ISSN)2470-9239

Journal ID (publisher-id): EPI4

Title: Epilepsia Open

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2470-9239

Publication date (Electronic): 05 August 2017

Publication date Collection: September 2017

Volume: 2

Issue: 3 ( doiID: 10.1111/epi4.2017.2.issue-3 )

Pages: 334-342

Affiliations

[ ¹ ] Department of Neurology and Epileptology Hertie‐Institute for Clinical Brain‐Research University of Tübingen Tübingen Germany

[ ² ] RKU‐University Neurology Clinic of Ulm Ulm Germany

[ ³ ] The Florey Institute of Neuroscience and Mental Health Melbourne Victoria Australia

[ ⁴ ] Department of Neurology and Epileptology University of Bonn Medical Center Bonn Germany

[ ⁵ ] School of Biosciences The University of Melbourne Melbourne Victoria Australia

[ ⁶ ] Department of Pharmacology University of Virginia Charlottesville Virginia U.S.A

[ ⁷ ]Present address: Illawarra Health and Medical Research Institute (IHMRI) University of Wollongong Wollongong New South Wales Australia

Author notes

[*] [* ]Address correspondence to Dr. Snezana Maljevic, The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, 3052 Vic., Australia. E‐mail: snezana.maljevic@ 123456florey.edu.au

[†]

Contributed equally.

Article

Publisher ID: EPI412068

DOI: 10.1002/epi4.12068

PMC ID: 5862120

PubMed ID: 29588962

SO-VID: 35cef6b7-7cac-4717-b203-a461fec048c5

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date accepted : 23 June 2017

Page count

Figures: 4, Tables: 1, Pages: 9, Words: 5571

Funding

Funded by: European Commission

Funded by: European Science Foundation

Funded by: DFG

Award ID: Le1030/11‐1

Funded by: Australian Government National Health and Medical Research Council (NHMRC)

Award ID: 10915693

Custom metadata

source-schema-version-number 2.0

component-id epi412068

cover-date September 2017

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.3 mode:remove_FC converted:21.03.2018

Keywords: hcn4,t‐type ca2+ channels,thalamo‐cortical circuits,generalized epilepsy

Data availability:

Keywords: hcn4, t‐type ca2+ channels, thalamo‐cortical circuits, generalized epilepsy

Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy

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Summary

Objective

Methods

Results

Significance

Related collections

Functional role of amyloid

Most cited references 43

Hyperpolarization-activated cation channels: from genes to function.

On the cellular and network bases of epileptic seizures.

Closed-loop optogenetic control of thalamus as a new tool to interrupt seizures after cortical injury

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