Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant dravet syndrome model during development
Journal
Neurobiology of Disease
Journal Volume
77
Pages
35-48
Date Issued
2015
Author(s)
Tsai M.-S.
Lee M.-L.
Chang C.-Y.
Fan H.-H.
Yu I.-S.
You J.-Y.
Chen C.-Y.
Chang F.-C.
Hsiao J.H.
Khorkova O.
HORNG-HUEI LIOU
Yanagawa Y.
Abstract
Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1. The nature and timing of changes caused by SCN1A mutation in the hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus and a classic epileptogenic zone, are not well known. In particularly, it is still not clear whether the developmental deficit of this epileptogenic neural network temporally matches with the progress of seizure development. Here, we investigated the emerging functional and structural deficits of the DG network in a novel mouse model (Scn1aE1099X/+) that mimics the genetic deficit of human DS. Scn1aE1099X/+ (Het) mice, similarly to human DS patients, exhibited early spontaneous seizures and were more susceptible to hyperthermia-induced seizures starting at postnatal week (PW) 3, with seizures peaking at PW4. During the same period, the Het DG exhibited a greater reduction of Nav1.1-expressing GABAergic neurons compared to other hippocampal areas. Het DG GABAergic neurons showed altered action potential kinetics, reduced excitability, and generated fewer spontaneous inhibitory inputs into DG granule cells. The effect of reduced inhibitory input to DG granule cells was exacerbated by heightened spontaneous excitatory transmission and elevated excitatory release probability in these cells. In addition to electrophysiological deficit, we observed emerging morphological abnormalities of DG granule cells. Het granule cells exhibited progressively reduced dendritic arborization and excessive spines, which coincided with imbalanced network activity and the developmental onset of spontaneous seizures. Taken together, our results establish the existence of significant structural and functional developmental deficits of the DG network and the temporal correlation between emergence of these deficits and the onset of seizures in Het animals. Most importantly, our results uncover the developmental deficits of neural connectivity in Het mice. Such structural abnormalities likely further exacerbate network instability and compromise higher-order cognitive processing later in development, and thus highlight the multifaceted impacts of Scn1a deficiency on neural development. ? 2015 Elsevier Inc.
SDGs
Other Subjects
4 aminobutyric acid receptor; glutamic acid; mutant protein; sodium channel Nav1.1; 4 aminobutyric acid; biocytin; glutamate decarboxylase; glutamate decarboxylase 1; lysine; Scn1a protein, mouse; sodium channel Nav1.1; animal cell; animal experiment; animal model; animal tissue; Article; controlled study; dendritic spine; dentate gyrus; developmental disorder; disease predisposition; female; functional disease; genetic disorder; granule cell; hippocampus; hyperthermia; male; mouse; nerve cell excitability; nerve potential; neurotransmission; nonhuman; perinatal period; priority journal; protein expression; seizure; severe myoclonic epilepsy in infancy; spontaneous seizure; structural deficit; action potential; adverse effects; age; analogs and derivatives; animal; chemical structure; disease model; drug effects; genetics; growth, development and aging; hyperthermic therapy; in vitro study; metabolism; mutation; myoclonus epilepsy; nerve cell; nerve cell network; newborn; pathology; pathophysiology; Seizures; transgenic mouse; ultrastructure; Action Potentials; Age Factors; Animals; Animals, Newborn; Dentate Gyrus; Disease Models, Animal; Epilepsies, Myoclonic; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Hyperthermia, Induced; In Vitro Techniques; Lysine; Male; Mice; Mice, Transgenic; Models, Molecular; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Nerve Net; Neurons; Seizures
Publisher
Academic Press Inc.
Type
journal article