Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice
| Autor: | Bruce F. O'Hara, Paul Franken, Robert D. Klein, Winston Thomas, Thadd Reeder, Theodore C. Dumas, Xinmin Xie, Judith Flores, Lamont Tang, Thomas J. Brennan, H. Craig Heller |
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| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Synaptic cleft Amino Acid Transport System y+ Genotype Hippocampus Sleep REM Biology In Vitro Techniques Synaptic Transmission Serine Mice Seizures Internal medicine Tremor medicine Animals Magnesium Cloning Molecular Receptor Molecular Biology Evoked Potentials Mice Knockout Behavior Animal Electromyography General Neuroscience Glutamate receptor Excitatory Postsynaptic Potentials Transporter Dose-Response Relationship Radiation Electroencephalography Electric Stimulation Death Endocrinology Animals Newborn Glycine Exploratory Behavior NMDA receptor Neurology (clinical) Developmental Biology |
| Zdroj: | Brain research. 1052(2) |
| ISSN: | 0006-8993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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