Impairment of N-methyl-D-aspartate receptor-controlled motor activity in LYN-deficient mice.
The N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor, is implicated in motor activity that is regulated in the striatum and nucleus accumbens of the brain. A Src family kinase Lyn is highly expressed in striatum, cortex, thalamus, and cerebellum in the brain. Here we show that spontaneous motor activity is suppressed in lyn-/- mice. S.c. injection of methylphenidate, which causes accumulation of dopamine in synapses, reveals that dopaminergic pathway is normal in lyn-/- mice. After blocking the NMDA receptor, motor activity of lyn-/- mice increased to the same level as that of wild type mice. Therefore, the NMDA receptor-mediated signaling is enhanced in lyn-/- mice, indicating that Lyn regulates the NMDA receptor pathway negatively. Intriguingly, the activity of protein kinase C (PKC), an enzyme regulated downstream of NMDA receptors, is increased in lyn-/- mice. The present data suggest that the NMDA receptor signal that is enhanced in the absence of Lyn suppresses the motor activity, probably through inhibition of dopaminergic pathway at striatum. We conclude that Lyn contributes to coordination of motor activity through regulation of the NMDA pathway. It appears that this negative regulation involves suppression of downstream signaling of NMDA receptor such as those mediated by PKC.
Umemori
H
H
Department of Oncology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ogura
H
H
Tozawa
N
N
Mikoshiba
K
K
Nishizumi
H
H
Yamamoto
T
T
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics*; D009433:Neural Inhibition / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D008774:Methylphenidate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D004298:Dopamine