Article: article from journal or magazin.
Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.
The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.
Amino Acid Transport System y+/deficiency, Amino Acid Transport System y+/genetics, Animals, Animals, Newborn, Behavior, Animal/physiology, Cloning, Molecular/methods, Death, Dose-Response Relationship, Radiation, Electric Stimulation, Electroencephalography/methods, Electromyography/methods, Evoked Potentials/drug effects, Evoked Potentials/physiology, Excitatory Postsynaptic Potentials/physiology, Excitatory Postsynaptic Potentials/radiation effects, Exploratory Behavior/physiology, Genotype, Hippocampus/physiopathology, Magnesium/pharmacology, Mice, Mice, Knockout/physiology, Seizures/genetics, Seizures/metabolism, Sleep, REM/physiology, Synaptic Transmission/genetics, Tremor/genetics, Tremor/metabolism
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