Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.

Détails

ID Serval
serval:BIB_D1788157402D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.
Périodique
Brain Research
Auteur⸱e⸱s
Xie X., Dumas T., Tang L., Brennan T., Reeder T., Thomas W., Klein R.D., Flores J., O'Hara B.F., Heller H.C., Franken P.
ISSN
0006-8993[print], 0006-8993[linking]
Statut éditorial
Publié
Date de publication
2005
Peer-reviewed
Oui
Volume
1052
Numéro
2
Pages
212-221
Langue
anglais
Résumé
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.
Mots-clé
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
Pubmed
Web of science
Création de la notice
24/01/2008 15:31
Dernière modification de la notice
20/08/2019 15:51
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