Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development.
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 (Scn1a(E1099X/+)) that mimics the genetic deficit of human DS. Scn1a(E1099X/+) (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.
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Ming-Shian
MS
Tsai
Department of Veterinary Medicine National Taiwan University, Taipei 100, Taiwan.
Meng-Larn
ML
Lee
National Institute on Drug Abuse (NIDA)-Intramural Research Program, Baltimore, MD 21224, USA.
Chun-Yun
CY
Chang
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Hsiang-Hsuan
HH
Fan
Laboratory animal center, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
I-Shing
IS
Yu
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
You-Tzung
YT
Chen
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Jhih-Yi
JY
You
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Chun-Yu
CY
Chen
Department of Veterinary Medicine National Taiwan University, Taipei 100, Taiwan.
Fang-Chia
FC
Chang
OPKO Health, Inc., Miami, FL 33137, USA.
Jane H
JH
Hsiao
OPKO Health, Inc., Miami, FL 33137, USA.
Olga
O
Khorkova
Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Horng-Huei
HH
Liou
Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Maebashi 371-8511, Japan.
Yuchio
Y
Yanagawa
Graduate Institute of Anatomy and Cell Biology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Brain and Mind Sciences, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: ljlee@ntu.edu.tw.
Li-Jen
LJ
Lee
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Center for Genomic Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: mtshuwha@ntu.edu.tw.
Shu-Wha
SW
Lin
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D018891:Dentate Gyrus / Q000254:growth & development / Q000473:pathology*; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006979:Hyperthermia, Induced / Q000009:adverse effects; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D009415:Nerve Net / Q000473:pathology*; D009474:Neurons / Q000648:ultrastructure; D012640:Seizures / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C013411:biocytin; D008239:Lysine
Dravet syndrome; Epilepsy; Mouse model; SCN1A