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 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.
Ng
David
D
Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Pitcher
Graham M
GM
Szilard
Rachel K
RK
Sertié
Andréa
A
Kanisek
Marijana
M
Clapcote
Steven J
SJ
Lipina
Tatiana
T
Kalia
Lorraine V
LV
Joo
Daisy
D
McKerlie
Colin
C
Cortez
Miguel
M
Roder
John C
JC
Salter
Michael W
MW
McInnes
Roderick R
RR
D000818:Animals; D002460:Cell Line; D004149:Dioxoles / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D004149:Dioxoles; D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C486748:Neto1 protein, mouse; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate