TY - JOUR
T1 - Murine succinate semialdehyde dehydrogenase deficiency
AU - Gupta, Maneesh
AU - Hogema, Boris M.
AU - Grompe, Markus
AU - Bottiglieri, Teodoro G.
AU - Concas, Alessandra
AU - Biggio, Giovanni
AU - Sogliano, Cristiana
AU - Rigamonti, Antonello E.
AU - Pearl, Phillip L.
AU - Snead, O. Carter
AU - Jakobs, Cornelis
AU - Gibson, K. Michael
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003
Y1 - 2003
N2 - 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 neuro- steroid levels in brain, potentially implicating the GABAA 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.
AB - 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 neuro- steroid levels in brain, potentially implicating the GABAA 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.
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U2 - 10.1002/ana.10625
DO - 10.1002/ana.10625
M3 - Article
C2 - 12891658
AN - SCOPUS:17144439967
SN - 0364-5134
VL - 54
SP - S81-S90
JO - Annals of Neurology
JF - Annals of Neurology
IS - SUPPL. 6
ER -