Differential gene expression in postnatal day 10 Scn1b+/+ vs. Scn1b -/- cortical layer VI
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE128573 | GEO | 2019/03/21
REPOSITORIES: GEO
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Project description:Scn1b null mice are a model of a severe developmental and epileptic encephalopathy called Dravet Syndrome (DS). The goal of this study was to identify changes in gene expression between Scn1b wild-type and Scn1b null mice before seizure onset (postnatal day 10)
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Project description:Dravet Syndrome (DS) is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. While different therapeutic strategies based on the upregulation of the healthy gene copy are being developed, repetitive seizures might lead to endurable and hardly treatable neural deficits. In fact, whether and to which extent this severe pathology is reversible after symptom onset remains unknown and the lack of this knowledge prevents the development of more effective therapies. We generated a novel Scn1a conditional knock-in mouse model (Scn1aStop) where Scn1a expression could be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with 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 reconstitution when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures and marked amelioration of behavioral abnormalities. Normalization of firing of hippocampal parvalbumin interneurons was observed after reactivation of the Scn1a mutant allele. We also identified dramatic gene expression alterations associated with astrogliosis in DS mice, rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological levels rescued epileptic seizures also in adult DS mice (P90) after months of repetitive seizure events. These results uncover the principles governing the reversibility of a severe epileptic encephalopathy as DS and they are central for accelerating therapeutic translation, providing key insights on the timing of delivery of the disease modifying therapies in DS.
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Project description:Dravet syndrome is a severe, early-onset epileptic encephalopathy frequently resulting from de novo mutations of SCN1A. Mice with heterozygous deletion of Scn1a (Scn1a+/-) model many features of Dravet syndrome, including spontaneous seizures and premature lethality. Scn1a+/- mice exhibit variable phenotype penetrance and expressivity dependent upon the strain background. On the 129S6/SvEvTac (129) strain, Scn1a+/- mice do not display an overt phenotype. However Scn1a+/- mice on the [129S6xB6]F1 strain (F1.Scn1a+/-) exhibit juvenile-onset spontaneous seizures and premature lethality. QTL mapping identified several modifier loci responsible for strain-dependent differences in survival of Scn1a+/- mice, but these loci do not account for all the observed phenotypic variance. Global RNA-seq analysis was performed to identify additional genes and pathways that may contribute to variable phenotypes. Hippocampal gene expression was analyzed in wild-type (WT) and Scn1a+/- mice on both F1 and 129 strains, at two time points during disease development. There were few gene expression differences between 129.WT and 129. Scn1a+/- mice and approximately 100 genes with small expression differences (6-36%) between F1.WT and F1.Scn1a+/- mice. Strain-specific gene expression differences were more pronounced, with dozens of genes with >1.5-fold expression differences between 129 and F1 strains. Age-specific and seizure-related gene expression differences were most prominent, with hundreds of genes with >2-fold differences in expression were identified between groups with and without seizures, suggesting potential differences in developmental trajectory and/or homeostatic plasticity during disease onset. Global expression differences in the context of Scn1a deletion may account for strain-dependent variation in seizure susceptibility and survival observed in Scn1a+/- mice.
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Project description:Dravet syndrome (DS) is a severe epileptic encephalopathy caused by heterozygous loss-of-function mutations in the SCN1A gene, indicating a haploinsufficient genetic mechanism underlining this pathology. Here, we tested whether dCas9-mediated Scn1a gene activation could rescue Scn1a haploinsufficiency and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screeened sgRNAs for their ability to stimulate Scn1a gene transcription in association with the dCas9 activation system. Interestingly, we identified one single sgRNA able to significantly increase Scn1a gene expression levels in cell lines as well as in primary neurons, with high specificity. Accordingly, levels of Nav1.1 protein were sufficiently augmented to potentiate firing ability of wild-type immature GABAergic interneurons. A similar effect in activating the Scn1a transcription was elicited in Dravet GABAergic interneurons rescuing their dysfunctional properties. To determine whether this approach could have therapeutic effect, we packaged adeno-associated viruses with the Scn1a-dCas9 activation system and showed their ability to ameliorate the febrile epileptic crises in DS mice. Our results pave the way for exploiting the dCas9-based gene activation as an effective and targeted approach to DS and other similar disorders resulting from altered gene dosage.
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Project description:dCas9-based Scn1a gene activation restores inhibitory interneuron excitability and restrains epileptic crises in Dravet syndrome mice
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Project description:Scn1b-/- mice are a model of Early Infantile Developmental Epileptic Encephalopathy (EIDEE). These mice exhibit characteristic seen in patients such as spontaneous siezures, ataxia, growth abnormalites, and a high incidence of premature mortality. The goal of this study was to identify changes in gene expression between Scn1b wild-type and Scn1b-/- mice in the atria
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Project description:Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
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