Human succinic semialdehyde dehydrogenase (SSADH) deficiency [ganmia-hydroxybutyric (GHB) aciduriaj is one of the tew neurogenetic disorders affecting the GABA neurotransmitter system, and one in which two neuroactive compounds, GAB A and GHB, accumulate. SSADH'''mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the clinical syndrome. Our main objectiveis to delineate basic mechanisms at play in the protean clinical manifestationsin SSADH deficiency. In the current project, we will address the following hypotheses (H) and aims (A): HI: pharmacotherapy broadly targeting the GABAergic/GHBergic receptor systems in SSADH"""""""""""""""" mice will extend lifespan and provide insight into treatment paradigms for humans. Al: To examine novel phurmacotherapeutics in SSADH""""""""''mice in order to rescue these animals from early lethality and explore neuropathology in surviving, adult mutants. H2. Absence seizures in SSADH""""""""'mice result from elevated GHB, whereas generalized convulsive seizures and status epilepticus arise from decreased GABAAR-mediatedinhibition induced by GABA-dependent down regulation of GABA^ receptors. A2.1) to assess the role of GHB in absence seizures and the role of absence seizures in the development of generalized convulsive seizures in SSADH'''mice, and to examine pharmacotherapeutics aimed at suppressing motor seizures and status epilepticus;A2.2) to define perturbations of the GABAA receptor (GABAAR) in SSADH""""""""'mice ? motor seizures and ? absence seizures and the relation of these to the onset of generalized convulsive seizures;A2.3) to ascertain GABAAR receptor conductances and the regulatory functions of GABABR receptors in SSADH""""""""'mice ? motor seizures and ? absence seizures;and 2.4) to determine the effect of excess GABA and/or GHB on GABAAR function and subunit composition. H3. Systemic GHB clearance is primarily limited by the total amount of SSADH activitypresent in liver.
Aim 3 : To perform liver repopulation with SSADH'"""""""" hepatocytes in SSADH** mice utilizing a selective growth advantage, in order to estimate the number of SSADH^ hepatocytes necessary to correct gamma-hydroxybutyric aciduria. The methods to achieve our objectives include therapeutics, neurophysiology and neurochemistry, and hepatocyte repopulation, among others. The SSADH""""""""'"""""""" mouse model represents a powerful investigativetool for understanding thepathophysiology associated with human SSADH deficiency. Our experimental approach possesses therapeutic import for human patients, and may have ramifications for understanding the fundamental mechanisms of epileptogenesis that extend far beyond SSADH deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS040270-08
Application #
7541805
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Tagle, Danilo A
Project Start
2000-09-30
Project End
2009-06-30
Budget Start
2009-01-01
Budget End
2009-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$86,356
Indirect Cost
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Malaspina, P; Roullet, J-B; Pearl, P L et al. (2016) Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem Int 99:72-84
Goodwin, Amy K; Gibson, K Michael; Weerts, Elise M (2013) Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): time course and severity of withdrawal in baboons. Drug Alcohol Depend 132:427-33
Siggberg, Linda; Mustonen, Aki; Schuit, Robert et al. (2011) Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity. Am J Med Genet B Neuropsychiatr Genet 156B:448-53
Pearl, Phillip L; Shukla, Lovy; Theodore, William H et al. (2011) Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. Brain Dev 33:796-805
Kim, Kyung-Jin; Pearl, Phillip L; Jensen, Kimmo et al. (2011) Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance. Antioxid Redox Signal 15:691-718
Wamelink, M M C; Roos, B; Jansen, E E W et al. (2011) 4-Hydroxybutyric aciduria associated with catheter usage: a diagnostic pitfall in the identification of SSADH deficiency. Mol Genet Metab 102:216-7
Errington, Adam C; Gibson, K Michael; Crunelli, Vincenzo et al. (2011) Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice. PLoS One 6:e19021
Knerr, Ina; Gibson, K Michael; Murdoch, Geoffrey et al. (2010) Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol 42:255-8
Vardya, Irina; Drasbek, Kim R; Gibson, K Michael et al. (2010) Plasticity of postsynaptic, but not presynaptic, GABAB receptors in SSADH deficient mice. Exp Neurol 225:114-22
Dósa, Zita; Nieto-Gonzalez, Jose Luis; Korshoej, Anders Rosendal et al. (2010) Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (gamma-hydroxybutyric aciduria). Epilepsy Res 90:39-46

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