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.
Xie
Xinmin
X
Deltagen Inc., San Carlos, CA 94070, USA. simonxie@afasci.com
Dumas
Theodore
T
Tang
Lamont
L
Brennan
Thomas
T
Reeder
Thadd
T
Thomas
Winston
W
Klein
Robert D
RD
Flores
Judith
J
O'Hara
Bruce F
BF
Heller
H Craig
HC
Franken
Paul
P
D027182:Amino Acid Transport System y+ / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D003001:Cloning, Molecular / Q000379:methods; D003643:Death; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology / Q000528:radiation effects; D005106:Exploratory Behavior / Q000502:physiology; D005838:Genotype; D006624:Hippocampus / Q000503:physiopathology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology*; D012640:Seizures / Q000235:genetics / Q000378:metabolism*; D012895:Sleep, REM / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics; D014202:Tremor / Q000235:genetics / Q000378:metabolism*
D027182:Amino Acid Transport System y+; C412624:Slc7a10 protein, mouse; D008274:Magnesium