Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior.
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.
Basu
A C
AC
Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA.
Tsai
G E
GE
Ma
C-L
CL
Ehmsen
J T
JT
Mustafa
A K
AK
Han
L
L
Jiang
Z I
ZI
Benneyworth
M A
MA
Froimowitz
M P
MP
Lange
N
N
Snyder
S H
SH
Bergeron
R
R
Coyle
J T
JT
D000161:Acoustic Stimulation / Q000379:methods; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001596:Benzylamines / Q000494:pharmacology; D001710:Biotin / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D019998:Racemases and Epimerases / Q000172:deficiency*; D045442:Rotarod Performance Test; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D000099300:Serine Racemase
D000779:Anesthetics, Local; D001596:Benzylamines; D001710:Biotin; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D008012:Lidocaine; D010721:Phosphinic Acids; D011810:Quinoxalines; D019998:Racemases and Epimerases; D000099300:Serine Racemase; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C083008:CGP 52432; C012647:QX-314