Universität zu Köln

Samehni, Mohamad (2023). Effects of the missense mutation (A263V) in the SCN2A gene on hippocampal and entorhinal cortex c-Fos expression in 7-day-old mice. PhD thesis, Universität zu Köln.

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Abstract

Voltage-gated sodium channels are transmembrane proteins that play a vital role in the initiation and propagation of action potentials in excitable cells and are the essential mediators of neuronal excitability. Dysfunction of voltage-gated sodium channels significantly affects brain development and plays a critical role in epileptogenesis. A genetic missense mutation in the SCN2A gene (A263V), which encodes the -subunit of the sodium channel Nav1.2, has been documented to cause neuronal hyperexcitability and to associate with benign familial neonatal infantile seizures and other therapy-resistant childhood epilepsy phenotypes. In this study, I aimed to characterize further the underlying mechanisms of brain circuitry alterations and the pathological substrate behind functional deficits caused by this mutation. I also aimed to find out if early postnatal treatment with a VGSC blocker could prevent the development of seizures and overcome the mutation effects. I studied the expression of c-Fos, an immediate early gene, as a marker of neuronal activation in the Hippocampus of Scn2a (A263V) mutant mice after treatment with phenytoin and controlled the results with my previous findings of not-treated ones. I also investigated the expression of c-Fos in the entorhinal cortex of mutant mice to determine if there was an increase in neuronal activation as an expected propagation region of neuronal hyperexcitability. My results showed decreased neuronal activation in the hippocampus of 7-day-old mutant mice after treatment with phenytoin, as demonstrated by lower c-Fos expression in both heterozygous and homozygous mutant mice. Taken together, even though prolonged treatment with phenytoin resulted in increased mortality in mutant mice, my results showed an efficient suppression of the mutation-triggered neuronal hyperexcitability at the hippocampus, the proposed origin of seizures in Scn2a (A263V) mutant mice. This study provides the basis for future analyses to investigate whether hyperexcitable neural circuitry in Scn2a (A263V) mutant mice leads to neurodegeneration and cell loss and for further treatment studies.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Samehni, Mohamad m.samehni@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-713681
Date:	2023
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language SCN2A English c-Fos English Epilepsy English
Date of oral exam:	31 May 2023
Referee:	Name Academic Title Isbrandt, Dirk Universitätsprofessor Dr. med. Sommerauer, Michael B. Privatdozent Dr. med.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71368