Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Abstract

Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cisinteractions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.synapse | neurotranmitter receptor | neurexin N MDA receptors (NMDARs) are key regulators of the development of neural circuits and synaptic plasticity (1, 2). In humans, perturbation of NMDAR function results in psychotic conditions, and genetic animal models with altered NMDAR activity exhibit phenotypes related to cognitive disorders such as schizophrenia and autism (3-5). Activity-dependent recruitment of NMDARs to synapses controls certain forms of synaptic plasticity (6, 7). However, the molecular mechanisms underlying the recruitment and physical tethering of NMDAR complexes at synapses are incompletely understood.Neuroligin-1 (NL1), one of four postsynaptic neuroligin adhesion molecules (NL1, 2, 3, 4), contributes to NMDAR regulation (8, 9). In cultured neurons, overexpression of NL1 promotes clustering of synaptic NMDARs (8), and NL1 KO mice show decreases in NMDAR-dependent excitatory postsynaptic currents (NMDAR EPSCs) (9-11). A major question in understanding neuroligin function is how specific isoforms couple to specific neurotransmitter receptors (12, 13). NMDARs were recovered in coimmunoprecipitations with NL proteins, indicating a potential complex formation, although in those experiments, no NL isoform-specificity was apparent (14). One candidate link between NLs and glutamate receptors is through postsynaptic scaffolding molecules such as postsynaptic density 95 (PSD95) (15, 16). However, all NL isoforms contain PSD95 binding sites, and NMDARs and PSD95 were recruited to NL1 with different time courses (14).Our results demonstrate that NL1 controls synaptic abundance of NMDAR via NL1-specific extracellular determinants. Loss of these interactions results in impairment of NMDAR-mediated transmission and synaptic plasticity. Our findings uncover an unexpected mode of NL1-NMDAR coupling and demonstrate a key role for the NL1 adhesion protein in the physical incorporation and retention of NMDAR at glutamatergic synapses.Results NL1-Specific Recruitment of NMDARs Does Not Require PSD95. We examined the specificity of molecular coupling of NL isoforms (NL1, 2, 3) to NMDARs by NL overexpression in cultured hippocampal neurons. NL1 increased the density of clusters of the NMDAR subunits GluN1, GluN2A, and GluN...

Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…In mice NLGN1 regulates the synaptic abundance of NMDAtype glutamate receptors (61). Overexpression of NLGN1 in mouse hippocampus results in increased inhibitory input and increases in glutamatergic neurotransmission (61,68). This finding is in good agreement with the excitation-inhibition hypothesis of schizophrenia, which posits that the NMDA receptor in the cortex functions as a kind of "excitatory sensor" and that decreased NMDA activity, particularly within interneurons, can lead to alteration of systems-level neural dynamics (69).…”

“…Several lines of evidence suggest an important role for NLGN1 in modulation of the NMDA-type glutamate receptor (61,67,68). In mice NLGN1 regulates the synaptic abundance of NMDAtype glutamate receptors (61). Overexpression of NLGN1 in mouse hippocampus results in increased inhibitory input and increases in glutamatergic neurotransmission (61,68).…”

“…The NLGN1-NRX complex has been found to specifically localize to glutamatergic synapses, where it helps stabilize the synapse and recruit additional synaptic proteins involved in synapse structure and function. Several lines of evidence suggest an important role for NLGN1 in modulation of the NMDA-type glutamate receptor (61,67,68). In mice NLGN1 regulates the synaptic abundance of NMDAtype glutamate receptors (61).…”

“…NLGN1 is a presynaptic adhesion protein with a critical role in synapse formation. There is increasing interest in the neuroligin family in schizophrenia because neuroligins form transsynaptic complexes with schizophreniaassociated neurexin (NRX) proteins (61,62). NLGN-NRX complexes are known to be important in brain development, and genetic variation in these genes has been associated with autism and schizophrenia (63)(64)(65)(66).…”

Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

“…Although it was initially thought that neuroligins are indispensable for synapse formation, research on NLGN1/2/3 triple KO mice has revealed that they are predominantly required for proper synapse maturation and brain function [6]. Many recent studies indicate that the role of neuroligins goes far beyond the simple scaffold formation, for example neuroligins can regulate such intrinsic synaptic functions as synaptic levels of NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [1,19,[21][22][23][24]. It has also been shown that nascent neurexin-neuroligin contacts rapidly capture surfacediffusing AMPARs at PSD-95 (postsynaptic density protein Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-018-1243-1) contains supplementary material, which is available to authorized users.…”