Developmental changes in brain activity of heterozygous Scn1a knockout rats

Mayu Tahara; Norimichi Higurashi; Junichi Hata; Masako Nishikawa; Ken Ito; Shinichi Hirose; Takehito Kaneko; Tomoji Mashimo; Tetsushi Sakuma; Takashi Yamamoto; Hirotaka James Okano

doi:10.3389/fneur.2023.1125089

Developmental changes in brain activity of heterozygous Scn1a knockout rats

Front Neurol. 2023 Mar 14:14:1125089. doi: 10.3389/fneur.2023.1125089. eCollection 2023.

Authors

Mayu Tahara^{1

2}, Norimichi Higurashi¹, Junichi Hata^{2

3}, Masako Nishikawa⁴, Ken Ito^{1

2}, Shinichi Hirose⁵, Takehito Kaneko⁶, Tomoji Mashimo⁷, Tetsushi Sakuma⁸, Takashi Yamamoto⁸, Hirotaka James Okano²

Affiliations

¹ Department of Pediatrics, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
² Division of Regenerative Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
³ Graduate School of Human Health Sciences, Tokyo Metropolitan University, Arakawa-ku, Tokyo, Japan.
⁴ Clinical Research Support Center, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
⁵ General Medical Research Center, School of Medicine, Fukuoka University, Fukuoka, Japan.
⁶ Division of Fundamental and Applied Sciences, Graduate School of Science and Engineering, Iwate University, Morioka, Japan.
⁷ Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
⁸ Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.

Abstract

Introduction: Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy characterized by an age-dependent evolution of drug-resistant seizures and poor developmental outcomes. Functional impairment of gamma-aminobutyric acid (GABA)ergic interneurons due to loss-of-function mutation of SCN1A is currently considered the main pathogenesis. In this study, to better understand the age-dependent changes in the pathogenesis of DS, we characterized the activity of different brain regions in Scn1a knockout rats at each developmental stage.

Methods: We established an Scn1a knockout rat model and examined brain activity from postnatal day (P) 15 to 38 using a manganese-enhanced magnetic resonance imaging technique (MEMRI).

Results: Scn1a heterozygous knockout (Scn1a ^+/-) rats showed a reduced expression of voltage-gated sodium channel alpha subunit 1 protein in the brain and heat-induced seizures. Neural activity was significantly higher in widespread brain regions of Scn1a ^+/- rats than in wild-type rats from P19 to P22, but this difference did not persist thereafter. Bumetanide, a Na⁺-K⁺-2Cl^- cotransporter 1 inhibitor, mitigated hyperactivity to the wild-type level, although no change was observed in the fourth postnatal week. Bumetanide also increased heat-induced seizure thresholds of Scn1a ^+/- rats at P21.

Conclusions: In Scn1a ^+/- rats, neural activity in widespread brain regions increased during the third postnatal week, corresponding to approximately 6 months of age in humans, when seizures most commonly develop in DS. In addition to impairment of GABAergic interneurons, the effects of bumetanide suggest a possible contribution of immature type A gamma-aminobutyric acid receptor signaling to transient hyperactivity and seizure susceptibility during the early stage of DS. This hypothesis should be addressed in the future. MEMRI is a potential technique for visualizing changes in basal brain activity in developmental and epileptic encephalopathies.

Keywords: Dravet syndrome (DS); bumetanide (BTN); developmental and epileptic encephalopathy (DEE); functional neuroimaging; gamma-aminobutyric acid (GABA).

Associated data

figshare/10.6084/m9.figshare.12894698