Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency
Open accessAbstract
Mice with targeted deletion of the GABA catabolic enzyme succinic semialdehyde dehydrogenase (SSADH) manifest lethal tonic-clonic seizures, amenable to pharmacologic rescue, at 3-4 weeks of life. In the current report, we characterized amino acid profiles in SSADH(-/-) brain utilizing whole brain and regional extracts (frontal and parietal cortex, hippocampus, and cerebellum) to develop hypotheses concerning epileptogenesis. Of 35 amino acids quantified, we found significant dysregulation in SSADH(-/-) mice for 11 (GABA, glutamate, glutamine, alanine, aspartate, serine, taurine, cystathionine, methionine, homocarnosine, and arginine) as compared to age-matched littermates both before, and following, the period of generalized convulsive seizures and status epilepticus. Our results reveal imbalanced amino acid levels potentially involved in the transition from absence seizures to generalized convulsive seizures resulting in SSADH(-/-) mice. We conclude that the SSADH(-/-) mouse represents a unique epileptic model with the potential to reveal novel aspects of excitatory/inhibitory interactions in the genesis of seizures.
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ALDH5A1 KO mice show increased cerebral aspartate levels, whereas previous studies reported unchanged aspartate amounts.
“Previous studies have reported unchanged aspartate amounts in the ALDH5A1 KO brain (Gibson et al., 2002;Gupta et al., 2004;Hogema et al., 2001), whereas we observed increased cerebral aspartate levels.”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Gupta et al., 2004
When SSADH fails to convert succinic semialdehyde into succinate, GABA accumulates in the brain.
“When SSADH fails to convert succinic semialdehyde into succinate, GABA accumulates in the brain (Afshar-Saber et al., 2024;Gibson et al., 2002;Gupta et al., 2004;Hogema et al., 2001;Kirby, Walters, Brown, et al., 2020)”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Gupta et al., 2004
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Andersen, J. V., Marian, O. C., Qvist, F. L., Westi, E. W., Aldana, B. I., Schousboe, A., Don, A. S., Skotte, N. H., & Wellendorph, P. (2024) · Glia · doi:10.1002/glia.24585 · Cited by 13 · see citing works
- Authors
- Gupta, M., Polinsky, M., Senephansiri, H., Snead, O. C., Jansen, E. E. W., Jakobs, C., & Gibson, K. M.
- Affiliations
- Oregon Health & Science University (US)
- Hospital for Sick Children (CA)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Gibson, K.M
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 16
- Issue
- 3
- Pages
- 556-562
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2073847757
- Cited by
- 56
- References
- 0
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- March of Dimes Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS040270, NS 40270)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- GABA catabolism, amino acid imbalance, epileptogenesis, seizure evolution, tonic-clonic seizures, status epilepticus, absence seizures, excitation-inhibition balance, glutamate, GABA, glutamine, glutathione, excitotoxicity
- MeSH terms
- Aldehyde Oxidoreductases, Amino Acids, Animals, Brain, Disease Models, Animal, Epilepsy, gamma-Aminobutyric Acid, Glutamine, Mice, Inbred C57BL, Neural Inhibition, Mice, Knockout, Glutamic Acid, Succinate-Semialdehyde Dehydrogenase, Mice
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