Murine Knockout Model of 4-Hydroxybutyric Aciduria

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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.