Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
- The University of Pennsylvania School of Medicine, United States
- The Children's Hospital of Philadelphia, United States
- Children's Hospital of Philadelphia, United States
- The University of Pennsylvania, United States
Abstract
Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach towards seizure modulation.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files for all Figures (1-8) and Tables (1-2) have been included and are also available via G-Node at:https://gin.g-node.org/GoldbergNeuroLab/Mattis-et-al-2022.Source code has been made available here:https://github.com/GoldbergNeuroLab/Mattis-et-al.-2022
-
Mattis-et-al-2022G_Node, 10.12751/g-node.jubxbd.
Article and author information
Author details
Ethan Michael Goldberg
Funding
National Institute of Neurological Disorders and Stroke (R25 NS065745)
- Joanna H Mattis
National Institute of Neurological Disorders and Stroke (K08 NS097633)
- Ethan Michael Goldberg
National Institute of Neurological Disorders and Stroke (R01 NS110869)
- Ethan Michael Goldberg
Dana Foundation (David Mahoney Neuroimaging Grant)
- Ethan Michael Goldberg
Burroughs Wellcome Fund (Career Award for Medical Scientists)
- Ethan Michael Goldberg
National Institute of Neurological Disorders and Stroke (K08 NS121464)
- Joanna H Mattis
Institute for Translational Medicine and Therapeutics (Translational Biomedical Imaging Center (TBIC))
- Joanna H Mattis
- Ethan Michael Goldberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Linda Overstreet-Wadiche, University of Alabama at Birmingham, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol 21-001152 of The Children's Hospital of Philadelphia. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Version history
- Received: April 10, 2021
- Preprint posted: May 1, 2021 (view preprint)
- Accepted: February 24, 2022
- Accepted Manuscript published: February 25, 2022 (version 1)
- Version of Record published: March 14, 2022 (version 2)
Copyright
© 2022, Mattis et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,366
- views
-
- 346
- downloads
-
- 26
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
eLife 11:e69293.
https://doi.org/10.7554/eLife.69293
Further reading
-
- Genetics and Genomics
- Neuroscience
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.
-
- Cancer Biology
- Genetics and Genomics
Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.
