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PNAS 103 (3): 762-767

Copyright © 2006 by the National Academy of Sciences.

NEUROSCIENCE

Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines

Lena Scott *, Sergey Zelenin *, Seth Malmersjö *, Jacob M. Kowalewski {dagger}, Eivor Zettergren Markus *, Angus C. Nairn {ddagger}, §, Paul Greengard §, Hjalmar Brismar *, {dagger}, and Anita Aperia *, ¶

*Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital Q2:09, S-171 76 Stockholm, Sweden; {dagger}Department of Cell Physics, Royal Institute of Technology, S-106 91 Stockholm, Sweden; {ddagger}Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519; and §Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021-6399

Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 18, 2005

Received for publication July 1, 2005.

Abstract: 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.

Key Words: organotypic cultures • fluorescence recovery after photo-bleaching • lateral diffusion • receptor movement

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: D1R, D1 receptor; FRAP, fluorescence recovery after photo-bleaching.

To whom correspondence should be addressed. E-mail: anita.aperia{at}kbh.ki.se.

© 2006 by The National Academy of Sciences of the USA

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