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

TitleLack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.
Publication TypeJournal Article
Year of Publication2005
JournalBrain research
Volume1052
Issue2
Pagination212-21
Date Published2005
ISSN0006-8993
Abstract

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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0006-8993(05)00922-4
DOI10.1016/j.brainres.2005.06.039
Short TitleBrain Res
X
Enter your linkblue username.
Enter your linkblue password.
Secure Login

This login is SSL protected

Loading