Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

Hammelmann, Verena; Stieglitz, Marc Sebastian; Hülle, Henrik; Meur, Karim Le; Kass, Jennifer; Brümmer, Manuela; Grüner, Christian; Rötzer, René D.; Fenske, Stefanie; Hartmann, Jana; Zott, Benedikt; Lüthi, Anita; Spahn, Saskia; Moser, Markus; Isbrandt, Dirk; Ludwig, A.; Konnerth, Arthur; Wahl‐Schott, Christian; Biel, Martin

doi:10.1172/jci.insight.126418

Cited by 24 publications

(30 citation statements)

References 69 publications

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“…This is in contrast with other studies that indicate that reductions in HCN2 channel activity in thalamocortical neurons induce generalized seizures (Chung et al, 2009; Hammelmann et al, 2019; Ludwig et al, 2003). Interestingly, while specific HCN2 channel knockout in the ventrobasal nuclei was sufficient to induce generalized seizures, HCN4 channel knockout was without effect (Hammelmann et al, 2019). This suggests that HCN2 and HCN4 subunits play distinct roles within thalamic neurons and that targeting each independently may produce different outcomes on excitability.…”

Section: Discussioncontrasting

confidence: 95%

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Kharouf

Phillips

Bleakley

et al. 2020

British J Pharmacology

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Background and Purpose Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are encoded by four genes (HCN1–4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti‐seizure strategy using pharmacological and genetic approaches. Experimental Approach The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. Key Results EC18 (10 mg·kg−1) and brain‐specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant‐mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant‐mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV‐HCN4 shRNA infected mouse cortical cultures. Conclusions and Implications These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti‐seizure drugs that is likely to have a low side‐effect liability in the CNS.

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Section: Discussioncontrasting

confidence: 95%

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Kharouf

Phillips

Bleakley

et al. 2020

British J Pharmacology

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“…Another interesting target could be the 5-HT2C receptor ( Di Giovanni and De Deurwaerdère, 2016 ), as selective agonists at these receptors have been shown to dose-dependently block experimental absence seizure ( Venzi et al , 2016 ). Finally, positive allosteric modulators of metabotropic glutamate receptors 1 and 5, which are key to cortico-thalamic transmission ( Baude et al , 1993 ; Romano et al , 1995 ; Errington et al , 2011 c ), block experimental absence seizures ( D’Amore et al , 2015 ; Celli et al , 2019 ), as does the selective thalamic block of hyperpolarization-activated, cyclic nucleotide-gated channels ( David et al , 2018 ) (see also Hammelmann et al , 2019 ; Zobeiri et al , 2019 ), opening up the possibility of selectively targeting one of these receptor/channel subtypes for treating CAE and other epilepsies with absence seizure.…”

Section: Introductionmentioning

confidence: 99%

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Crunelli

Lőrincz

McCafferty

et al. 2020

Brain

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Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

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“…Furthermore, there is evidence from preclinical studies using knock down models that HCN2 and HCN4 channels form heterotetramers (Hammelmann et al, 2019). It is therefore somewhat J o u r n a l P r e -p r o o f surprising that the HCN2/1-preferring drug, MEL55A, exacerbates seizure susceptibility while the HCN4-preferring drug, EC18, is protective.…”

Section: The Impact Of Isoform-preferring Hcn Channel Blockers On Seimentioning

confidence: 99%

“…Similarly, viral-vector-mediated targeted deletion in mice indicate that thalamic deletion of HCN2 results in spike-and-wave discharges (Hammelmann et al, 2019). In contrast, conditional brain and thalamic targeted knockout of HCN4 channels does not cause spike-and-wave discharges in mice (Hammelmann et al, 2019;Kharouf et al, 2020;Zobeiri et al, 2019).…”

Section: The Impact Of Isoform-preferring Hcn Channel Blockers On Seimentioning

confidence: 99%

Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice

et al. 2020

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Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

Cited by 24 publications

References 69 publications

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice

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