Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines.
The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We show here that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines. Using organotypic culture from rat striatum transfected with D1R fused to a fluorescent protein, we show that the majority of dendritic D1R are in lateral diffusion and that their mobility is confined by interaction with NMDA receptors. Exposure to NMDA reduces the diffusion coefficient for D1R and causes an increase in the number of D1R-positive spines. Unexpectedly, the action of NMDA in potentiating D1R recruitment was independent of calcium flow via the NMDA receptor channel. Thus, a highly energy-efficient, diffusion-trap mechanism can account for intraneuronal interaction between the glutamatergic and dopaminergic systems and for regulation of the number of D1R-positive spines. This diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy.
Scott
Lena
L
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital Q2:09, S-171 76 Stockholm, Sweden.
Zelenin
Sergey
S
Malmersjö
Seth
S
Kowalewski
Jacob M
JM
Markus
Eivor Zettergren
EZ
Nairn
Angus C
AC
Greengard
Paul
P
Brismar
Hjalmar
H
Aperia
Anita
A
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism*; D004058:Diffusion; D036681:Fluorescence Recovery After Photobleaching; D017930:Genes, Reporter; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate