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Molecular and Cellular Biology, October 2004, p. 8872-8883, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.8872-8883.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Neuronal LRP1 Functionally Associates with Postsynaptic Proteins and Is Required for Normal Motor Function in Mice

Petra May,1,2,3*,{dagger} Astrid Rohlmann,1,{dagger},{ddagger} Hans H. Bock,1,2,3 Kai Zurhove,1,3 Jamey D. Marth,4 Eike D. Schomburg,5 Jeffrey L. Noebels,6 Uwe Beffert,1 J. David Sweatt,7 Edwin J. Weeber,7,§ and Joachim Herz1,3

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas,1 Department of Neurology,6 Division of Neuroscience, Baylor College of Medicine, Houston, Texas,7 Department of Medicine II,2 Zentrum für Neurowissenschaften, University of Freiburg, Freiburg,3 Center of Physiology and Pathophysiology, Georg-August University, Göttingen, Germany,5 Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California4

Received 16 June 2004/ Accepted 13 July 2004

The LDL receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor that is highly expressed on neurons. Neuronal LRP1 in vitro can mediate ligand endocytosis, as well as modulate signal transduction processes. However, little is known about its role in the intact nervous system. Here, we report that mice that lack LRP1 selectively in differentiated neurons develop severe behavioral and motor abnormalities, including hyperactivity, tremor, and dystonia. Since their central nervous systems appear histoanatomically normal, we suggest that this phenotype is likely attributable to abnormal neurotransmission. This conclusion is supported by studies of primary cultured neurons that show that LRP1 is present in close proximity to the N-methyl-D-aspartate (NMDA) receptor in dendritic synapses and can be coprecipitated with NMDA receptor subunits and the postsynaptic density protein PSD-95 from neuronal cell lysates. Moreover, treatment with NMDA, but not dopamine, reduces the interaction of LRP1 with PSD-95, indicating that LRP1 participates in transmitter-dependent postsynaptic responses. Together, these findings suggest that LRP1, like other ApoE receptors, can modulate synaptic transmission in the brain.

* Corresponding author. Mailing address: Zentrum für Neurowissenschaften, University of Freiburg, Albertstraße 23, 79104 Freiburg, Germany. Phone: 49-(0)761-203 8421. Fax: 49-(0)761-203 8433. E-mail: Petra.May{at}zfn.uni-freiburg.de.

{dagger} P.M. and A.R. contributed equally to this study.

{ddagger} Present address: Center of Physiology and Pathophysiology, Georg-August University, 37073 Göttingen, Germany.

§ Present address: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232-0615.

Molecular and Cellular Biology, October 2004, p. 8872-8883, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.8872-8883.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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