scholarly journals Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicholas Valassina ◽  
Simone Brusco ◽  
Alessia Salamone ◽  
Linda Serra ◽  
Mirko Luoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Symptom Onset ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Neurological Deficits ◽  
Behavioral Alterations ◽  
Unexpected Death ◽  
Physiological Level ◽  
Behavioral Abnormalities

AbstractDravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome

2020 ◽  
Vol 12 (558) ◽  
pp. eaaz6100 ◽  
Author(s):  
Zhou Han ◽  
Chunling Chen ◽  
Anne Christiansen ◽  
Sophina Ji ◽  
Qian Lin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Antisense Oligonucleotides ◽  
De Novo ◽  
Nuclear Gene ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Unexpected Death ◽  
Α Subunit ◽  
Gene And Protein Expression ◽  
Electrographic Seizures

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a+/− × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Changing Landscape of Dravet Syndrome Management: An Overview

2020 ◽  
Vol 51 (02) ◽  
pp. 135-145 ◽  
Author(s):  
Debopam Samanta
Keyword(s):  
Motor Impairment ◽  
Current Treatment ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Loss Of Function ◽  
Unexpected Death ◽  
Autistic Behavior ◽  
Behavioral Abnormalities ◽  
Treatment Paradigm ◽  
Antisense Oligonucleotide Therapy

AbstractDravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe developmental and epileptic encephalopathy caused by loss-of-function mutations in one copy of SCN1A (haploinsufficiency), located on chromosome 2q24, with decreased function of Nav1.1 sodium channels in GABAergic inhibitory interneurons. Pharmacoresistant seizures in DS start in the infancy in the form of hemiclonic febrile status epilepticus. Later, other intractable seizure types develop including myoclonic seizures. Early normal development in infancy evolves into moderate to severe intellectual impairment, motor impairment, behavioral abnormalities, and later a characteristic crouching gait. Clobazam, valproate, levetiracetam, topiramate, zonisamide, ketogenic diet, and vagus nerve stimulation had been shown to be effective, but even with polytherapy, only 10% of patients get adequate seizure control. The author provides a narrative review of the current treatment paradigm as well as recent advances in the management of DS based on a comprehensive literature review (MEDLINE using PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. In recent years, the treatment paradigm of DS is changing with the approval of pharmaceutical-grade cannabidiol oil and stiripentol. Another novel antiepileptic drug (AED), fenfluramine, had also shown excellent efficacy in phase 3 studies of DS. However, these AEDs primarily control seizures without addressing the underlying pathogenesis and other important common comorbidities such as cognitive impairment, autistic behavior, neuropsychiatric abnormalities, and motor impairment including crouching gait. Several agents targeted for DS are in the developmental stage: TAK935, lorcaserin, clemizole, huperzine analog, ataluren, selective sodium channel modulators and activators, antisense oligonucleotide therapy, and adenoviral vector therapy. As DS is associated with a high risk of sudden unexpected death in epilepsy, seizure detection devices can be used in this population for testing and clinical validation of these devices.

Adolescent behavioral abnormalities in a Scn1a+/− mouse model of Dravet syndrome

2020 ◽  
Vol 103 ◽  
pp. 106842
Author(s):  
Dilara Bahceci ◽  
Lyndsey Leigh Anderson ◽  
Cassandra Veronica Occelli Hanbury Brown ◽  
Cilla Zhou ◽  
Jonathon Carl Arnold
Keyword(s):  
Mouse Model ◽  
Dravet Syndrome ◽  
Behavioral Abnormalities

scholarly journals Sudden unexpected death in a mouse model of Dravet syndrome

2013 ◽  
Vol 123 (4) ◽  
pp. 1798-1808 ◽  
Author(s):  
Franck Kalume ◽  
Ruth E. Westenbroek ◽  
Christine S. Cheah ◽  
Frank H. Yu ◽  
John C. Oakley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sudden Unexpected Death ◽  
Dravet Syndrome ◽  
Unexpected Death

scholarly journals VPA Alleviates Neurological Deficits and Restores Gene Expression in a Mouse Model of Rett Syndrome

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e100215 ◽  
Author(s):  
Weixiang Guo ◽  
Keita Tsujimura ◽  
Maky Otsuka I. ◽  
Koichiro Irie ◽  
Katsuhide Igarashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Neurological Deficits

scholarly journals Electrophysiological Alterations of Pyramidal Cells and Interneurons of the CA1 Region of the Hippocampus in a Novel Mouse Model of Dravet Syndrome

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 1055-1066
Author(s):  
David A. Dyment ◽  
Sarah C. Schock ◽  
Kristen Deloughery ◽  
Minh Hieu Tran ◽  
Kerstin Ure ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mouse Model ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Resting Membrane Potential ◽  
Sodium Currents ◽  
Spike Amplitude ◽  
Induced Neurons

Dravet syndrome is a developmental epileptic encephalopathy caused by pathogenic variation in SCN1A. To characterize the pathogenic substitution (p.H939R) of a local individual with Dravet syndrome, fibroblast cells from the individual were reprogrammed to pluripotent stem cells and differentiated into neurons. Sodium currents of these neurons were compared with healthy control induced neurons. A novel Scn1aH939R/+ mouse model was generated with the p.H939R substitution. Immunohistochemistry and electrophysiological experiments were performed on hippocampal slices of Scn1aH939R/+ mice. We found that the sodium currents recorded in the proband-induced neurons were significantly smaller and slower compared to wild type (WT). The resting membrane potential and spike amplitude were significantly depolarized in the proband-induced neurons. Similar differences in resting membrane potential and spike amplitude were observed in the interneurons of the hippocampus of Scn1aH939R/+ mice. The Scn1aH939R/+ mice showed the characteristic features of a Dravet-like phenotype: increased mortality and both spontaneous and heat-induced seizures. Immunohistochemistry showed a reduction in amount of parvalbumin and vesicular acetylcholine transporter in the hippocampus of Scn1aH939R/+ compared to WT mice. Overall, these results underline hyper-excitability of the hippocampal CA1 circuit of this novel mouse model of Dravet syndrome which, under certain conditions, such as temperature, can trigger seizure activity. This hyper-excitability is due to the altered electrophysiological properties of pyramidal neurons and interneurons which are caused by the dysfunction of the sodium channel bearing the p.H939R substitution. This novel Dravet syndrome model also highlights the reduction in acetylcholine and the contribution of pyramidal cells, in addition to interneurons, to network hyper-excitability.

scholarly journals Astrocyte Ca2+ Signaling is Facilitated in an Scn1a+/− Mouse Model of Dravet Syndrome

2021 ◽  
Author(s):  
Kouya Uchino ◽  
Wakana Ikezawa ◽  
Yasuyoshi Tanaka ◽  
Masanobu Deshimaru ◽  
Kaori Kubota ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sodium Channel ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Heterozygous Mutation ◽  
Loss Of Function ◽  
Cell Type ◽  
Voltage Gated ◽  
A Subunit ◽  
The Brain

Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A, which encodes a subunit of the voltage-gated sodium channel, Nav1.1, in neurons. The roles played by astrocytes, the most abundant glial cell type in the brain, have been investigated in the pathogenesis of epilepsy; however, the specific involvement of astrocytes in DS has not been clarified. In this study, we evaluated Ca2+ signaling in astrocytes using genetically modified mice that have a loss-of-function mutation in Scn1a. We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/− astrocytes. In addition, ATP-induced transient Ca2+ influx and the slope of Ca2+ spiking were also increased in Scn1a+/− astrocytes. These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS.

scholarly journals Gene expression profiling in a mouse model of Dravet syndrome

2019 ◽  
Vol 311 ◽  
pp. 247-256 ◽  
Author(s):  
Nicole A. Hawkins ◽  
Jeffrey D. Calhoun ◽  
Alexandra M. Huffman ◽  
Jennifer A. Kearney
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Dravet Syndrome

scholarly journals Synaptic and intrinsic mechanisms impair reticular thalamus and thalamocortical neuron function in a Dravet syndrome mouse model

2021 ◽  
Author(s):  
Carleigh Studtmann ◽  
Marek Ladislav ◽  
Mackenzie A. Topolski ◽  
Mona Safari ◽  
Sharon A. Swanger
Keyword(s):  
Mouse Model ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
List Type ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Cortical Input ◽  
Neuron Populations ◽  
Firing Properties ◽  
Synaptic Mechanisms

ABSTRACTThalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel NaV1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that NaV1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced intrinsic excitability in nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. NaV1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced ascending glutamatergic sensory input to VPL neurons, but not VPM neurons. In addition, glutamatergic cortical input to nRT neurons was reduced in Scn1a heterozygous mice, whereas cortical input to VPL and VPM neurons remained unchanged. These findings introduce input-specific alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in Dravet syndrome, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in Dravet syndrome and identifies new components of corticothalamic circuitry as potential therapeutic targets.HIGHLIGHTSGABAergic reticular thalamus neurons have impaired tonic and burst firing properties in a NaV1.1 haploinsufficiency mouse model of Dravet syndrome.NaV1.1 haploinsufficiency has opposing effects on spike firing in two distinct glutamatergic thalamocortical neuron populations.NaV1.1 haploinsufficiency alters glutamatergic synaptic connectivity in an input-specific manner in the thalamus.Dysregulation of both intrinsic and synaptic mechanisms contribute to imbalanced thalamic excitation and inhibition in this Dravet syndrome mouse model.

Sign in / Sign up

Export Citation Format

Share Document