Abstract
A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation / methods
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Anesthetics, Local / pharmacology
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology*
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Benzylamines / pharmacology
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Biotin / metabolism
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Chromatography, High Pressure Liquid / methods
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Excitatory Postsynaptic Potentials / physiology*
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GABA Antagonists / pharmacology
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Glutamic Acid / metabolism*
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Hippocampus / cytology
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In Vitro Techniques
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Inhibition, Psychological
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Lidocaine / analogs & derivatives
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Lidocaine / pharmacology
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Maze Learning / drug effects
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Maze Learning / physiology
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Memory Disorders / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Neurons / physiology
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Patch-Clamp Techniques
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Phosphinic Acids / pharmacology
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Psychomotor Performance / drug effects
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Psychomotor Performance / physiology
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Quinoxalines / pharmacology
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Racemases and Epimerases / deficiency*
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Rotarod Performance Test
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Space Perception / drug effects
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Space Perception / physiology
Substances
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Anesthetics, Local
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Benzylamines
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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Phosphinic Acids
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Quinoxalines
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2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
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CGP 52432
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QX-314
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Glutamic Acid
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Biotin
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Lidocaine
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Racemases and Epimerases
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serine racemase