TY - JOUR
T1 - Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice
AU - May, Petra
AU - Rohlmann, Astrid
AU - Bock, Hans H.
AU - Zurhove, Kai
AU - Marth, Jamey D.
AU - Schomburg, Eike D.
AU - Noebels, Jeffrey L.
AU - Beffert, Uwe
AU - Sweatt, J. David
AU - Weeber, Edwin J.
AU - Herz, Joachim
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=4744352010&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4744352010&partnerID=8YFLogxK
U2 - 10.1128/MCB.24.20.8872-8883.2004
DO - 10.1128/MCB.24.20.8872-8883.2004
M3 - Article
C2 - 15456862
AN - SCOPUS:4744352010
SN - 0270-7306
VL - 24
SP - 8872
EP - 8883
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 20
ER -