Murine Knockout Model of 4-Hydroxybutyric Aciduria

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DESCRIPTION (provided by applicant): Human succinic semialdehyde dehydrogenase (SSADH) deficiency [gamma-hydroxybutyric (GHB) aciduria] is one of the few neurogenetic disorders affecting the GABA neurotransmitter system, and one in which two neuroactive compounds, GABA and GHB, accumulate. SSADH-/- mice manifest early absence seizures that evolve into lethal generalized convulsive epilepsy, comparable to pediatric patients with absence epilepsy whose seizures follow a similar clinical evolution. Our long-term objective is to delineate basic mechanisms at play in the protean pathology manifested in SSADH deficiency, and to develop novel preclinical treatment paradigms, through evaluation of the following hypotheses (H) and aims (A): HI. Disruption of the neuronal-glial glutamate/GABA/glutamine axis, oxidant stress and the accumulation of toxic carbonyls underlie the transition of absence seizures into generalized convulsions in the SSADH-/- mouse. A1. To characterize glutamate/GABA/glutamine neurotransmitter cycling between neurons and astroglia, oxidant stress, and carbonyl accumulation in the pathology of the SSADH / mouse. H2. Perturbed GABA-mediated neurotransmission causes generalized absence seizures to evolve into generalized convulsive seizures. A2. To define the developmental critical window for the transition of absence seizures to generalized convulsive seizures in SSADH/ mice, assess GABAAR- and GABABR-mediated function during this critical transition period, and determine whether over-expression of GABABR1 will rescue these animals from the onset of generalized convulsive seizures. 1-13. Systemic gamma-hydroxybutyrate clearance is primarily limited by the total amount of SSADH activity present in liver. A3. To perform liver repopulation with SSADW-/- hepatocytes in SSADH+/+ mice utilizing a selective growth advantage. Elucidation of biochemical and neurochemical pathology, and evaluation of long-term enzyme replacement in the mouse model, work in unison toward our long-term objective. The methods to achieve our objectives include biochemical measurements, magnetic resonance spectroscopy, neurophysiology, receptor binding, hepatocyte repopulation, and mouse breeding among others. Our studies in murine SSADH deficiency possess broad clinical relevance: 1) biochemical and neurochemical characterization of pathology is directly pertinent to human SSADH deficiency; 2) determining the mechanism of seizure evolution will provide novel insight into the transition from absence to generalized convulsive seizures in children with absence epilepsy; and 3) understanding alterations of the GABA/glutamate/glutamine axis will provide pathomechanistic insight into other epileptic and neuropsychiatric disorders in which this axis is likely disturbed.