Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.
The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane pr...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-02-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19243221/?tool=EBI |
| _version_ | 1818932083714686976 |
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| author | David Ng Graham M Pitcher Rachel K Szilard Andréa Sertié Marijana Kanisek Steven J Clapcote Tatiana Lipina Lorraine V Kalia Daisy Joo Colin McKerlie Miguel Cortez John C Roder Michael W Salter Roderick R McInnes |
| author_facet | David Ng Graham M Pitcher Rachel K Szilard Andréa Sertié Marijana Kanisek Steven J Clapcote Tatiana Lipina Lorraine V Kalia Daisy Joo Colin McKerlie Miguel Cortez John C Roder Michael W Salter Roderick R McInnes |
| author_sort | David Ng |
| collection | DOAJ |
| description | The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans. |
| first_indexed | 2024-12-20T04:26:51Z |
| format | Article |
| id | doaj.art-3b93d0508888458dabaff426a1a4130a |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-20T04:26:51Z |
| publishDate | 2009-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-3b93d0508888458dabaff426a1a4130a2022-12-21T19:53:29ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-02-0172e4110.1371/journal.pbio.1000041Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.David NgGraham M PitcherRachel K SzilardAndréa SertiéMarijana KanisekSteven J ClapcoteTatiana LipinaLorraine V KaliaDaisy JooColin McKerlieMiguel CortezJohn C RoderMichael W SalterRoderick R McInnesThe N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19243221/?tool=EBI |
| spellingShingle | David Ng Graham M Pitcher Rachel K Szilard Andréa Sertié Marijana Kanisek Steven J Clapcote Tatiana Lipina Lorraine V Kalia Daisy Joo Colin McKerlie Miguel Cortez John C Roder Michael W Salter Roderick R McInnes Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biology |
| title | Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. |
| title_full | Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. |
| title_fullStr | Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. |
| title_full_unstemmed | Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. |
| title_short | Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. |
| title_sort | neto1 is a novel cub domain nmda receptor interacting protein required for synaptic plasticity and learning |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19243221/?tool=EBI |
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