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Murine succinate semialdehyde dehydrogenase deficiency
Author(s) -
Gupta Maneesh,
Hogema Boris M.,
Grompe Markus,
Bottiglieri Teodoro G.,
Concas Alessandra,
Biggio Giovanni,
Sogliano Cristiana,
Rigamonti Antonello E.,
Pearl Phillip L.,
Snead O. Carter,
Jakobs Cornelis,
Gibson K. Michael
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10625
Subject(s) - neuroactive steroid , biology , knockout mouse , gabaa receptor , gamma aminobutyric acid , central nervous system , pharmacology , endocrinology , medicine , receptor , biochemistry
Inherited succinic semialdehyde dehydrogenase (SSADH) deficiency (γ‐hydroxybutyric aciduria) is one of the few neurogenetic disorders of GABA metabolism, and one in which tonic‐clonic seizures associate with increased central nervous system GABA and γ‐hydroxybutyrate (GHB). To explore pathomechanisms and develop new preclinical treatment approaches, we developed a murine knockout model of SSADH deficiency. In the absence of intervention, SSADH −/− mice suffer 100% mortality at week 3 to 4 of life from generalized tonic‐clonic seizures. In this report, we summarize earlier studies indicating disruption of the GABA/glutamine axis in SSADH −/− mouse brain, effective pharmacotherapeutic approaches, preliminary gene‐therapy results, and electrophysiological analyses of mutant mice. We also present new evidence for oxidative stress in SSADH −/− mice, significant alterations of dopamine metabolism, and abnormal neurosteroid levels in brain, potentially implicating the GABA A receptor in pathogenesis. In SSADH deficiency, the accumulation of two neuroactive species, GABA and GHB, is significant because GABA is one of the earliest transmitters expressed in mammals, with key roles in synaptogenesis and myelination, whereas GHB displays a vast array of pharmacological actions. The SSADH −/− mouse may represent a useful model in which to explore the effect of GABA and GHB accumulation on central nervous system development and function. Ann Neurol 2003;54 (suppl 6):S81–S90