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.
Highlights
In the mammalian central nervous system, excitatory transmission at synapses is mediated primarily by the amino acid glutamate, acting through the postsynaptic a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartic acid receptors (NMDARs) [1]
We found that neuropilin tolloid-like 1 (Neto1) immunostaining decorated MAP2 positive dendritic arbors and co-localized with that of postsynaptic density (PSD)-95 (Figure 2B) and NR1 (Figure 2C)
These findings demonstrate that Neto1 is a component of the PSD of excitatory synapses
Summary
In the mammalian central nervous system, excitatory transmission at synapses is mediated primarily by the amino acid glutamate, acting through the postsynaptic a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartic acid receptors (NMDARs) [1]. Basal synaptic transmission is principally mediated by AMPARs, which are rapidly activated by glutamate, while the more slowly activated NMDAR primarily mediates various forms of synaptic plasticity. The core NMDAR is a heterotetramer comprised of two obligate NR1 subunits and two NR2(A-D) subunits [1]. These core subunits are embedded in a multiprotein complex that includes more than 70 NMDAR-associated proteins [4]. An emerging theme in NMDAR biology is that proteins associated with the core NMDAR may have important roles in the trafficking, stability, subunit composition, or function of NMDARs and may be critical for synaptic plasticity, learning, and memory [5]. Proteins that function to maintain synaptic NMDARs, which are wellknown for AMPARs, have been elusive for NMDARs
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