Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome

eLife

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[1] Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States;Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, United States;Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States;Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States;The Medical Scientist Training Program, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States;

关键词: epilepsy;    Nav1.1;    SCN1A;    electrophysiology;    ion channels;    Mouse;   

DOI  :  10.7554/eLife.46846

来源: publisher

【 摘 要 】

10.7554/eLife.46846.001Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (Scn1a+/-) mice. However, the function of a third major class of interneurons in DS – those expressing vasoactive intestinal peptide (VIP-IN) –is unknown. We recorded VIP-INs in brain slices from Scn1a+/-mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in Scn1a+/- mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis.

【 授权许可】

CC BY