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

TITLE=Developmental changes in brain activity of heterozygous Scn1a knockout rats

JOURNAL=Frontiers in Neurology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1125089

DOI=10.3389/fneur.2023.1125089

ISSN=1664-2295

ABSTRACT=<sec><title>Introduction</title><p>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 <italic>SCN1A</italic> 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 <italic>Scn1a</italic> knockout rats at each developmental stage.</p></sec><sec><title>Methods</title><p>We established an <italic>Scn1a</italic> knockout rat model and examined brain activity from postnatal day (P) 15 to 38 using a manganese-enhanced magnetic resonance imaging technique (MEMRI).</p></sec><sec><title>Results</title><p><italic>Scn1a</italic> heterozygous knockout (<italic>Scn</italic>1<italic>a</italic><sup>+/−</sup>) 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 <italic>Scn</italic>1<italic>a</italic><sup>+/−</sup> rats than in wild-type rats from P19 to P22, but this difference did not persist thereafter. Bumetanide, a Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> 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 <italic>Scn</italic>1<italic>a</italic><sup>+/−</sup> rats at P21.</p></sec><sec><title>Conclusions</title><p>In <italic>Scn</italic>1<italic>a</italic><sup>+/−</sup> 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.</p></sec>