Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
Abstract Dravet syndrome (DS) is a neurodevelopmental disorder defined by treatment-resistant epilepsy, autism spectrum disorder, and sudden death, due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit. Convergent data suggest hippocampal dentate gyrus (DG) pathology. We found that optogenetic stimulation of entorhinal cortex was ictogenic in DS (Scn1a+/-) but not wild-type mice in vivo. Two-photon calcium imaging in brain slice demonstrated profound impairment in filtering of perforant path input by DG in young adult Scn1a+/- mice due to enhanced excitatory input to granule cells. Excitability of parvalbumin interneurons (PV-INs) was near-normal and selective activation of PV-INs rescued circuit impairments. This demonstrates developmental reorganization of hippocampal circuitry that can be modulated by recruitment of functional PV-INs, suggesting potential therapeutic approaches towards seizure modulation. The identified circuit abnormality mirrors that seen in models of chronic temporal lobe epilepsy, suggesting convergent mechanisms linking genetic and acquired causes of temporal lobe-onset seizures.
Kaneko Keisuke、Goff Kevin M.、Yom Jina、Feng Huijie、Goldberg Ethan M.、Mattis Joanna、Somarowthu Ala、McGarry Laura M.、Sotuyo Nathaniel P.
Division of Neurology, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaNeuroscience Graduate Group, The University of Pennsylvania Perelman School of MedicineCollege of Arts and Sciences, The University of PennsylvaniaDivision of Neurology, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaDepartment of Neurology, The Perelman School of Medicine at The University of Pennsylvania||Division of Neurology, Department of Pediatrics, The Children?ˉs Hospital of Philadelphia||Department of Neuroscience, The Perelman School of Medicine at The University of PennsylvaniaDepartment of Neurology, The Perelman School of Medicine at The University of PennsylvaniaDivision of Neurology, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaDivision of Neurology, Department of Pediatrics, The Children?ˉs Hospital of PhiladelphiaNeuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine
基础医学神经病学、精神病学分子生物学
Kaneko Keisuke,Goff Kevin M.,Yom Jina,Feng Huijie,Goldberg Ethan M.,Mattis Joanna,Somarowthu Ala,McGarry Laura M.,Sotuyo Nathaniel P..Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2021.05.01.442271.点此复制
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