Neto1 Is a Novel CUB-Domain NMDA Receptor-Interacting Protein Required for Synaptic Plasticity and Learning

作者：Ng David; Pitcher Graham M; Szilard Rachel K; Sertie Andrea; Kanisek Marijana; Clapcote Steven J; Lipina Tatiana; Kalia Lorraine V; Joo Daisy; McKerlie Colin; Cortez Miguel; Roder John C; Salter Michael W^*; McInnes Roderick R

来源：PLOS BIOLOGY, 2009, 7(2): 278-300.

DOI：10.1371/journal.pbio.1000041

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.

• 出版日期2009-2
• 单位河北医科大学