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1.
Mol Psychiatry ; 14(7): 719-27, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19065142

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.


Subject(s)
Behavior, Animal/physiology , Excitatory Postsynaptic Potentials/physiology , Glutamic Acid/metabolism , Racemases and Epimerases/deficiency , Acoustic Stimulation/methods , Anesthetics, Local/pharmacology , Animals , Behavior, Animal/drug effects , Benzylamines/pharmacology , Biotin/metabolism , Chromatography, High Pressure Liquid/methods , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , GABA Antagonists/pharmacology , Hippocampus/cytology , In Vitro Techniques , Inhibition, Psychological , Lidocaine/analogs & derivatives , Lidocaine/pharmacology , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Neurons/physiology , Patch-Clamp Techniques , Phosphinic Acids/pharmacology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Quinoxalines/pharmacology , Rotarod Performance Test , Space Perception/drug effects , Space Perception/physiology
2.
Neuromuscul Disord ; 15(11): 779-85, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16198105

ABSTRACT

Utrophin is an autosomal homologue of dystrophin, abnormal expression of which is responsible for X-linked Duchenne and Becker muscular dystrophy. In normal mature muscle utrophin is confined to blood vessels, nerves and myotendinous and neuromuscular junctions. When dystrophin is absent utrophin is abundant on the sarcolemma. This has raised the possibility that up-regulation of utrophin may be of therapeutic benefit. Two full-length transcripts of utrophin, A and B, have been identified, which are regulated by alternatively spliced 5' promoters. In dystrophic mouse muscle, the A isoform is present on the sarcolemma, whereas the B form is confined to blood vessels. We show here using immunohistochemistry and human isoform-specific antibodies that A- and B-utrophin localisation is the same in human muscle. The A isoform is present on the sarcolemma of foetal human muscle fibres, regenerating fibres, fibres deficient in dystrophin and on blood vessels and neuromuscular junctions. B-utrophin is only detected on blood vessels. We also show that muscle adjacent to some soft tissue tumours shows increased sarcolemmal utrophin-A, showing that utrophin and dystrophin can simultaneously localise to the sarcolemma and raising the possibility that factor(s) from the tumour cells or accompanying inflammatory cells may have a role in regulating utrophin.


Subject(s)
Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/metabolism , Neoplasms/metabolism , Sarcolemma/metabolism , Utrophin/metabolism , Adolescent , Dystrophin/metabolism , Embryo, Mammalian , Humans , Immunohistochemistry/methods , Infant , Intercellular Signaling Peptides and Proteins , Nerve Tissue Proteins , Protein Isoforms/metabolism , Proteins/metabolism , Utrophin/classification
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