Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development.

摘要: 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 mutation of the SCN1A gene, which encodes voltage-gated sodium channel subunit Na v 1.1. The nature timing changes caused in hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus classic epileptogenic zone, are not well known. In particularly, it still clear whether developmental deficit this neural network temporally matches progress seizure development. Here, we investigated emerging functional structural deficits DG novel mouse model ( Scn1a E1099X/+ ) that mimics genetic human DS. (Het) mice, similarly DS patients, exhibited early spontaneous seizures were more susceptible hyperthermia-induced starting at postnatal week (PW) 3, peaking PW4. During same period, Het greater reduction 1.1-expressing GABAergic neurons compared other areas. showed altered action potential kinetics, reduced excitability, generated fewer inhibitory inputs into granule cells. effect cells was exacerbated transmission elevated release probability these addition electrophysiological deficit, observed morphological abnormalities progressively dendritic arborization excessive spines, coincided imbalanced activity onset seizures. Taken together, our results establish existence significant temporal correlation between emergence animals. Most importantly, uncover connectivity mice. Such likely further exacerbate instability compromise higher-order cognitive processing later development, thus highlight multifaceted impacts deficiency on