A proteomic analysis of NMDA receptor–adhesion protein signaling complexes was conducted using mass spectrometry and immunoblotting to characterize NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins, including receptor, adaptor, signaling, cytoskeletal, and novel proteins. Of these, 30 were implicated from binding studies, and another 19 participated in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins, and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impaired learning, while interference with 22 proteins altered synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition. The study identified 77 proteins in the NRC, including NMDAR subunits, PSD-95, Chapsyn-110, and other signaling proteins. The NRC was found to contain kinases, phosphatases, and other proteins involved in synaptic plasticity and learning. The NRC was also found to include adhesion and structural proteins, such as N-Cadherin, Desmoglein, and L1. These proteins may be involved in structural organization of the NRC at the synapse. The NRC was also found to include proteins involved in Ras signaling, including H-Ras, Rap2, and NF1. The study also identified several proteins involved in the MAPK pathway, including ERK1, ERK2, and c-Raf1. The NRC was found to contain proteins involved in synaptic plasticity and learning, including Arg3.1/Arc, Homer, and HSP70. The study also identified several proteins involved in the regulation of synaptic plasticity, including cPLA2 and PTP1D/SHP2. The NRC was found to contain proteins involved in the regulation of actin cytoskeleton, including α-actinin 2 and spectrin. These proteins are involved in NMDAR channel properties, NMDAR-mediated LTP, and NMDAR localization. The study also identified several proteins involved in the regulation of cell-adhesion molecules, including N-Cadherin, Desmoglein, and L1. These proteins may be involved in structural organization of the NRC at the synapse. The NRC was found to contain proteins involved in the regulation of synaptic plasticity, including cPLA2 and PTP1D/SHP2. The study also identified severalA proteomic analysis of NMDA receptor–adhesion protein signaling complexes was conducted using mass spectrometry and immunoblotting to characterize NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins, including receptor, adaptor, signaling, cytoskeletal, and novel proteins. Of these, 30 were implicated from binding studies, and another 19 participated in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins, and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impaired learning, while interference with 22 proteins altered synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition. The study identified 77 proteins in the NRC, including NMDAR subunits, PSD-95, Chapsyn-110, and other signaling proteins. The NRC was found to contain kinases, phosphatases, and other proteins involved in synaptic plasticity and learning. The NRC was also found to include adhesion and structural proteins, such as N-Cadherin, Desmoglein, and L1. These proteins may be involved in structural organization of the NRC at the synapse. The NRC was also found to include proteins involved in Ras signaling, including H-Ras, Rap2, and NF1. The study also identified several proteins involved in the MAPK pathway, including ERK1, ERK2, and c-Raf1. The NRC was found to contain proteins involved in synaptic plasticity and learning, including Arg3.1/Arc, Homer, and HSP70. The study also identified several proteins involved in the regulation of synaptic plasticity, including cPLA2 and PTP1D/SHP2. The NRC was found to contain proteins involved in the regulation of actin cytoskeleton, including α-actinin 2 and spectrin. These proteins are involved in NMDAR channel properties, NMDAR-mediated LTP, and NMDAR localization. The study also identified several proteins involved in the regulation of cell-adhesion molecules, including N-Cadherin, Desmoglein, and L1. These proteins may be involved in structural organization of the NRC at the synapse. The NRC was found to contain proteins involved in the regulation of synaptic plasticity, including cPLA2 and PTP1D/SHP2. The study also identified several