Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/26212
Title: Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy.
Austin Authors: Bleakley, Lauren E;McKenzie, Chaseley E;Soh, Ming S;Forster, Ian C;Pinares-Garcia, Paulo;Sedo, Alicia;Kathirvel, Anirudh;Churilov, Leonid ;Jancovski, Nikola;Maljevic, Snezana;Berkovic, Samuel F ;Scheffer, Ingrid E ;Petrou, Steven;Santoro, Bina;Reid, Christopher A
Affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia
Epilepsy Research Centre
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, VIC, Australia
Department of Neuroscience, The Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
Issue Date: 1-Apr-2021
metadata.dc.date: 2021-04-01
Publication information: Brain 2021; online first: 1 April
Abstract: Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L mouse. Lamotrigine exacerbated seizures and increased spiking, whereas sodium valproate reduced spiking, mirroring drug responses reported in a patient with this variant. Functional analysis in Xenopus laevis oocytes and layer V somatosensory cortical pyramidal neurons in ex vivo tissue revealed a loss of voltage dependence for the disease variant resulting in a constitutively open channel that allowed for cation 'leak' at depolarised membrane potentials. Consequently, Hcn1M294L layer V somatosensory cortical pyramidal neurons were significantly depolarised at rest. These neurons adapted through a depolarising shift in action potential threshold. Despite this compensation, layer V somatosensory cortical pyramidal neurons fired action potentials more readily from rest. A similar depolarised resting potential and left-shift in rheobase was observed for CA1 hippocampal pyramidal neurons. The Hcn1M294L mouse provides insight into the pathological mechanisms underlying hyperexcitability in HCN1 developmental and epileptic encephalopathy, as well as being a preclinical model with strong construct and face validity, on which potential treatments can be tested.
URI: https://ahro.austin.org.au/austinjspui/handle/1/26212
DOI: 10.1093/brain/awab145
PubMed URL: 33822003
Type: Journal Article
Subjects: HCN channels
developmental and epileptic encephalopathy
epilepsy
genetic mouse model
ion channel
Appears in Collections:Journal articles

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