Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.
Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.
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缺乏丙氨酸-丝氨酸-半胱氨酸转运蛋白 1 会导致小鼠震颤、癫痫发作和产后早期死亡。
DOI：
10.1016/j.brainres.2005.06.039
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Franken,Paul
中科院分区：
文献类型：
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作者：
Xie,Xinmin;Dumas,Theodore;Tang,Lamont;Brennan,Thomas;Reeder,Thadd;Thomas,Winston;Klein,RobertD;Flores,Judith;O'Hara,BruceF;Heller,HCraig;Franken,Paul
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 (Ki: 8–12 μM), 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 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.
