Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.
PLoS Biol
; 7(2): e41, 2009 Feb 24.
Article
em En
| MEDLINE
| ID: mdl-19243221
ABSTRACT
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Receptores de N-Metil-D-Aspartato
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Transmissão Sináptica
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Aprendizagem
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Lipoproteínas LDL
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Proteínas de Membrana
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Plasticidade Neuronal
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
PLoS Biol
Assunto da revista:
BIOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Canadá