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

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.

Neto2 is a KCC2 interacting protein required for neuronal Cl − regulation in hippocampal neurons

“…We elucidated the role of this association and characterized its importance in the normal neurophysiological function of KCC2. Because Neto proteins were previously identified as auxiliary subunits of ionotropic glutamate receptors, including kainate and NMDA receptors (17)(18)(19)(20)(21), this study further extends the role of the Neto proteins to inhibitory synapses.…”

“…Recent reports have demonstrated that Neto2 and its homologous protein Neto1 have important functions at excitatory synapses. Neto1 interacts with both the N-methyl D-aspartate receptor (NMDAR) and kainate receptor complexes (17,20,22), whereas Neto2 was shown to be an auxiliary subunit of the neuronal kainate receptor (18,(21)(22)(23). As the Neto proteins appear to have multiple functions in the nervous system, we chose to explore additional roles these proteins might have by conducting an unbiased screen to identify proteins that interact with the Neto proteins.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Neto1 possesses a single transmembrane domain containing two complement C1r/C1s, Uegf, Bmp1 domains and is a component of the NMDA receptor complex (Ng et al, 2009). Neto1 interacts with an extracellular domain of GluN2 as well as through an intracellular interaction with PSD95.…”

Exciting Times: New Advances Towards Understanding the Regulation and Roles of Kainate Receptors

“…PSD95 also binds to the auxiliary subunit Neto1 [84], and accelerates the recovery of GluK2 from desensitisation [85]. The KAR component of the EPSC at MF-CA3 synapses is reduced in PSD95 knockout mice, suggesting a role for this interaction in KAR synaptic localisation [86].…”