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

Abstract

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.

We thank Wen-Ling Niu and Huichuan Reyna for excellent technical assistance.

P.M. received an Emmy-Noether Fellowship from the Deutsche Forschungsgemeinschaft (DFG). A.R. was the recipient of a fellowship from the DFG. U.B. received fellowships from the Canadian Institutes of Health Research and the Human Frontier Science Program. This study was supported by grants from the NIH (HL20948, HL63762, and NS43408), the Alzheimer Association, the Perot Family Foundation, and the Wolfgang Paul Program of the Humboldt Foundation.