1. -Epilepsy and the use of rodent animal models for study.
Neurobiology.
SCN1A
Sodium voltage-gated channel alpha subunit 1.
Jamie Levitt
30001532
Sheffield Hallam university
Biosciences
2. 1
Codes for an essential sodium channel subtype permitting
The extracellular influx of sodium
Present predominantly in the brain (Purkinje cells, ganglion
cells)
Highly susceptible to a variety of mutations.
SCN1A within the nervous system.
Fig 1. The distribution of Nav1.1 sodium channels heavily
concentrated along the axon and soma of a neuron. (Mael
Demenieu, Marie Oule et al., 2017)
Fig 2. Membrane potential graph displaying the impact of a
sodium channels function upon electrical charge. (Michael
Grider, Rishita Jessu et al.,2023)
Fig 3. Nav1.1 protein structure coded for by the SCN1A. (Ian
Miller, Marcio Sotero de Menezes, 2007)
Fig 4. Nav1.1 protein diagram with mutation sites and types
present. (HuiHui Sun, Yuehua Zhang et al.2010)
1
3
4
2
3. 2
Mutations and their impacts.
Over 1800 know mutations
85% of mutations responsible for Dravet syndrome
Responsible for a number of life altering epilepsies.
5
6
Fig 5. A comparison set of experiments analysing the differences
in action potential between a healthy set of Nav1.1 channels and
channels affected by a Dravet inducing mutation. (A+B) Maximal
action potential output. (C+D) Dynamic action potential output.
(E+F) Maximal frequency rate of action potential firing. (G+H)
Input-output dynamic of the action potential. (Yishan Sun, Sergiu
P Pasca, et al., 2016)
Fig 6. Known possible Nav1.1 mutations along the subunit
including the related illnesses associated. (Jiangwei Ding, Xinxiao
Li, et al., 2021)
4. 3
Studying Dravet through animal models.
Gene manipulation techniques allow for the
Of rodent genetic code
High susceptibility to heat induced epilepsy.
Mutated sodium channels result in chemical imbalances
Leading to premature mortality
7
Fig 7. Utilising gene manipulation techniques in rodents to create a
suitable population of test subjects for further Dravet syndrome
experimentation. (A) Experimental process. (B) Specific exon targeting
utilising ribonucleoprotein. (C) Endonuclease assay. (D) Genome editing
processes. E Offspring result of genome editing. (F) Sanger sequencing
discovering a stop codon in mutated offspring. (Miao Li, Lixing Yai, Et
al. 2023)
Fig 8. Mutated offspring reliably obtains Dravet syndrome, as a result
regular temperature induced epilepsy ensue in further experimenting.
(A)Thermal induction protocol. (B) Comparison between mutated and
healthy rodents. (C) Behavioural changes and seizure intensity. (D)
Probability of seizure development in mutated rats. E Temperature after
thermal induction had ceased. (F) Rate of temperature increase in mutated
and healthy rats. (Miao Li, Lixing Yai, Et al. 2023)
8
5. 4
Dravet and treatments
Currently vastly approached by multi
Drug therapy.
Gene manipulation therapies in development.
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11
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Fig 9. Known mechanisms of currently used anti epilepsy drugs. ( Adam
streclzyk, Susanne Schubert-Bast, 2022)
Figure 10. The use of viral vector to transfer healthy SCN1A gene into
mutated rodents. (Lucia Mora-Jimenez, Miguel Valencia, et al., 2021)
Figure 11. Sodium currents from mutated HCA-EF-SCN1A-GFP(left)
Sodium currents from mutated HCA-EF-SCN1A-GFP after Hm1a peptide
addition. (Lucia Mora-Jimenez, Miguel Valencia, et al., 2021)
Figure 12. EEGs taken from mutated subjects post healthy gene addition.
(Lucia Mora-Jimenez, Miguel Valencia, et al., 2021)
6. 5
Bibliography
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Systematic Review and Narrative Synthesis. Frontiers neurobiology.(Vol 12.) https://doi.org/10.3389/fneur.2021.743726
Dumenieu M., Oule M., Kreutz R. M., Lopez Rohas J., 2017. The Segregated Expression of Voltage-Gated Potassium and Sodium Channels
in Neuronal Membranes: Functional Implications and Regulatory Mechanisms. Frontiers cellular neuroscience. (vol 11)
https://doi.org/10.3389/fncel.2017.00115
Grider M., Jessu R., Kabir R., 2023. Physilogy, action potential. Statpearls. https://pubmed.ncbi.nlm.nih.gov/30844170/
Li, M., Yang, L., Qian, W., Ray, S., Lu, Z., Liu, T., Zou, Y. Y., Naumann, R. K., & Wang, H. (2023). A novel rat model of Dravet syndrome
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Miller, I. O., & Sotero de Menezes, M. A. (2007). SCN1A Seizure Disorders. In M. P. Adam (Eds.) et. al., GeneReviews®. University of
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