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Succinic semialdehyde dehydrogenase deficiency: GABAB receptor-mediated function
Andrea Buzzi1, Ying Wu, Marina V Frantseva
1Brain and Behavior Program, Faculty of Medicine, University of Toronto, ON, Canada.
Brain Research
|May 2, 2006
Summary
Succinic semialdehyde dehydrogenase (SSADH) deficiency in mice leads to elevated gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB). This impairs GABAB receptor function, potentially explaining seizures and cognitive deficits in SSADH deficiency.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Succinic semialdehyde dehydrogenase (SSADH) deficiency is a metabolic disorder causing neurological symptoms.
- Elevated brain gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB) are hallmarks of SSADH deficiency.
- GHB may act as a GABAB receptor agonist at high concentrations.
Purpose of the Study:
- To investigate the impact of SSADH deficiency on GHB and GABAB receptor (GABABR) function.
- To determine if GABABR binding and function are altered in SSADH-deficient mice.
Main Methods:
- Utilized SSADH null mice (SSADH(-/-)) as a model for human SSADH deficiency.
- Assessed GABABR binding using a specific antagonist ([3H]CGP-54626A).
- Measured GABABR-mediated synaptic potentials and GABABR subunit protein expression via immunoblotting.
Main Results:
- SSADH(-/-) mice showed significantly decreased GABABR antagonist binding, particularly in the hippocampus.
- GABABR-mediated synaptic potentials were reduced in SSADH(-/-) mice.
- A trend towards decreased GABABR subunit protein expression was observed in SSADH(-/-) mice.
Conclusions:
- Elevated GABA and GHB in SSADH deficiency cause a use-dependent decrease in GABABR function.
- Perturbation of GABABR signaling may contribute to seizures and mental retardation in SSADH deficiency.
- GHBR function remains unaffected in SSADH-deficient mice.