Developmental Changes in Brain Activity in scn1a Knockout Rats: Analysis Using Manganese-enhanced Magnetic Resonance Imaging
Abstract number :
3.26
Submission category :
5. Neuro Imaging / 5B. Functional Imaging
Year :
2022
Submission ID :
2204136
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Mayu Tahara, MD – The Jikei University School of Medicine; Junichi Hata, PhD – Tokyo Metropolitan University; Norimichi Higurashi, MD, PhD – The Jikei University School of Medicine; Shinichi Hirose, MD, PhD – Fukuoka University; Ken Ito, MD – The Jikei University School of Medicine; Takehito Kaneko, PhD – Iwate University; Tomoji Mashimo, PhD – University of Tokyo; Masako Nishikawa, PhD – The Jikei University School of Medicine; Hirotaka Okano, MD, PhD – The Jikei University School of Medicine; Tetsushi Sakuma, PhD – Hiroshima University; Takashi Yamamoto, PhD – Hiroshima University
Rationale: To characterize age-dependent changes in regional brain activity of Scn1a knockout rats.
Methods: We established an Scn1a knockout rats and performed manganese-enhanced magnetic resonance imaging technique (MEMRI) at each developmental stage from the second to fifth postnatal week. Regional neural activity was statistically compared between heterozygous and wild-type rats using T1 mapping.
Results: Heterozygous Scn1a rats recapitulated the key phenotypic features of Dravet syndrome (DS), including reduced expression of the NaV1.1 protein in the brain and heat-induced seizures. Spontaneous convulsive seizures were observed from the fourth postnatal week. MEMRI showed significantly higher neural activity in widespread brain regions of heterozygous Scn1a rats compared to wild-type rats during the third postnatal week. The difference disappeared during the fourth postnatal week, and the brain regions with high neural activity were localized to several brain regions during the fifth postnatal week. Daily administration of an NKCC1 inhibitor to heterozygous Scn1a rats improved the increased neural activity in widespread brain regions and significantly increased the heat-induced seizure threshold; however, these effects were not observed during the fourth postnatal week.
Conclusions: In heterozygous 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. The effects of bumetanide suggest a possible contribution of immature GABAA receptor signalling on the transient hyperactivity, seizure susceptibility, and DS development. The localized neural activity observed during the fifth postnatal week in heterozygous Scn1a rats may be related to some prepubertal clinical features of DS, including epilepsy as well as nonepileptic manifestations, such as motor disorders and cognitive impairment. MEMRI can be a potential technique to visualize changes in basal brain activity in developmental and epileptic encephalopathies.
Funding: This work was supported in part by JSPS KAKENHI Grants, AMED under Grant Number JP21ek0109505, grants from the Science Research Promotion Funds, research grants from Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, The Mother and Child Health Foundation, and The Japan Epilepsy Research Foundation.
Neuro Imaging