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 mu M), two endogerrous 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 clelft. Asc-1 may play an important role in controlling neuronal excitability. We generated ase-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-l(-/-) 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 Mg2+-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. (c) 2005 Elsevier B.V. All rights reserved.