Affinage

NLGN2

Neuroligin-2 · UniProt Q8NFZ4

Length
835 aa
Mass
90.8 kDa
Annotated
2026-04-29
82 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLGN2 is a postsynaptic cell-adhesion molecule that organizes and maintains GABAergic inhibitory synapses by forming trans-synaptic complexes with presynaptic neurexins and recruiting the scaffolding protein gephyrin and GABAA receptors to postsynaptic sites. Its extracellular cholinesterase-like domain, which homodimerizes and binds both α- and β-neurexins, determines exclusive inhibitory-synapse localization and is competitively regulated by MDGA1, whose compact ectodomain sterically occludes the neurexin-binding surface of the NLGN2 dimer (PMID:28641112, PMID:39284869, PMID:39747663). The cytoplasmic tail operates through a gephyrin-dependent mechanism (disrupted by the autism-associated R705C mutation) and a parallel gephyrin-independent pathway involving S714 phosphorylation, while surface levels are sustained by SNX27-mediated endosomal recycling and regulated by NMDA-receptor-triggered proteolytic cleavage and FMRP-dependent translational control of Nlgn2 mRNA (PMID:27805570, PMID:31775031, PMID:30056576). Loss of NLGN2 function—whether by knockout, the schizophrenia-linked R215H mutation that causes ER retention, or peptide disruption of the neurexin interface—reduces inhibitory transmission across brain regions including hippocampus, amygdala, mPFC, and nucleus accumbens, producing anxiety, cognitive impairment, altered social behavior, and stress susceptibility (PMID:21551456, PMID:29859117, PMID:25824299, PMID:29339486, PMID:41802868).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 High

    Establishing that NLGN2 requires surface delivery for synaptogenic function: the R215H missense variant causes ER retention, abolishing GABAergic synaptogenesis, and NRXN2 truncations that cannot bind NLGN2 similarly fail to induce synaptic differentiation, defining the neurexin–NLGN2 trans-synaptic interaction as necessary for inhibitory synapse formation.

    Evidence Immunocytochemistry and electrophysiology in neuron coculture with mutant NLGN2 (R215H) and truncated NRXN2 constructs

    PMID:21424692 PMID:21551456

    Open questions at the time
    • Mechanism of ER quality control for NLGN2 folding mutants undefined
    • Whether other NLGN2 missense variants cause similar retention unknown
  2. 2013 Medium

    Identifying transcriptional regulation of NLGN2: promoter dissection revealed CpG-rich elements with cell-type-specific activity and MeCP2-dependent and -independent regulation, while hippocampal peptide disruption of NLGN2–neurexin binding showed that this interaction regulates social behavior.

    Evidence Reporter gene assays with NLGN2 promoter constructs and MeCP2 binding analysis; intra-hippocampal neurolide-2 peptide injection with behavioral readouts in rats

    PMID:23875667 PMID:24213355

    Open questions at the time
    • Endogenous transcription factor occupancy at NLGN2 promoter not mapped
    • Peptide specificity for NLGN2 versus other neuroligins not fully established
  3. 2014 Medium

    Revealing competitive binding on presynaptic neurexins: α-dystroglycan and NLGN2 compete for binding to α-neurexin-1 at overlapping LNS domains, providing a mechanism by which presynaptic factors gate inhibitory synapse identity.

    Evidence Site-directed mutagenesis of Nrxn1α LNS domains with cell-based binding competition assays

    PMID:25157101

    Open questions at the time
    • In vivo relevance of dystroglycan–NLGN2 competition at inhibitory synapses not tested
    • Whether competition is regulated by activity unknown
  4. 2015 High

    Demonstrating that NLGN2 is required for ongoing maintenance—not just initial formation—of inhibitory synapses in the adult brain: conditional KO in adult mPFC caused progressive (6–7 week) loss of synaptic inhibition and cognitive/social impairment.

    Evidence Adult conditional KO via stereotaxic viral Cre delivery; electrophysiology, immunostaining, and behavioral battery over weeks

    PMID:25824299

    Open questions at the time
    • Molecular cascade linking NLGN2 loss to delayed synapse disassembly unknown
    • Whether maintenance role generalizes beyond mPFC not established at this time point
  5. 2016 High

    Dissecting the domain logic of NLGN2: the extracellular domain confers inhibitory-synapse specificity and localization, while two distinct cytoplasmic mechanisms—gephyrin-dependent (disrupted by R705C) and gephyrin-independent (requiring S714)—are both essential for inhibitory synaptic function; in the amygdala, NLGN2 localizes to perisomatic inhibitory synapses and its deletion causes disinhibition of projection neurons under anxiogenic conditions.

    Evidence Chimeric and point-mutant NLGN2 constructs with electrophysiology in rat CA1; Nlgn2 KO mouse amygdala electrophysiology and cFOS mapping; spinal cord splice-variant analysis

    PMID:26142252 PMID:26859820 PMID:27805570

    Open questions at the time
    • Kinase responsible for S714 phosphorylation not identified
    • Whether gephyrin-dependent and -independent pathways converge on same downstream effectors unknown
  6. 2017 High

    Structural basis for MDGA1-mediated NLGN2 regulation resolved: MDGA1 Ig1-Ig2 domains bind the NLGN2 dimer at the neurexin-binding surface with nanomolar affinity, sterically blocking trans-synaptic bridge formation.

    Evidence Crystal structure of MDGA1 Ig1-Ig2 in complex with NLGN2 dimer; site-directed mutagenesis and binding affinity measurements

    PMID:28641112

    Open questions at the time
    • Whether MDGA1 binding is dynamically regulated at synapses unknown
    • Structure of full-length MDGA1–NLGN2 complex not resolved
  7. 2018 High

    Multiple studies established circuit-level and post-translational regulation: NLGN2 loss in D1 versus D2 NAc neurons produces opposite stress phenotypes; NLGN2 associates with SERT in midbrain modulating serotonergic function; FMRP binds Nlgn2 mRNA controlling local synaptic translation; NMDA receptor activation triggers NLGN2 proteolytic cleavage; IgSF9b operates epistatically with NLGN2 in amygdala anxiety circuits; R215H knock-in mice recapitulate schizophrenia-like phenotypes.

    Evidence Cell-type-specific viral KD in D1/D2-Cre mice; reciprocal Co-IP of NLGN2–SERT; RNA immunoprecipitation for FMRP–Nlgn2 mRNA; NMDA stimulation cleavage assay; double-KO epistasis (Nlgn2×IgSF9b); R215H knock-in mouse electrophysiology and behavior

    PMID:26793096 PMID:29339486 PMID:29859117 PMID:30056576 PMID:30573727 PMID:30605713

    Open questions at the time
    • Protease responsible for NMDA-triggered NLGN2 cleavage not identified
    • Molecular link between IgSF9b and NLGN2 pathway unclear
    • Whether SERT interaction is direct or scaffold-mediated at atomic level unresolved
  8. 2019 High

    Endosomal recycling and human disease relevance established: SNX27 binds the NLGN2 PDZ-binding motif to recycle internalized NLGN2 back to the synaptic surface, maintaining GABAA receptor clusters; in iPSC-derived human cortical interneurons from schizophrenia patients, reduced NLGN2 levels correlate with synaptic deficits that are rescued by NLGN2 overexpression.

    Evidence Co-IP and SNX27 KD with electrophysiology readout; iPSC-derived interneurons with bidirectional NLGN2 manipulation and synaptic puncta quantification

    PMID:31775031 PMID:31780643

    Open questions at the time
    • Whether SNX27-NLGN2 recycling is activity-dependent not tested
    • Genetic causality of NLGN2 reduction in schizophrenia patient lines not established
  9. 2022 Medium

    Cryo-EM structure of the human NLGN2 extracellular domain revealed a homodimeric architecture with a distinct protomer rotation compared to NLGN3, suggesting structural basis for differential MDGA recognition.

    Evidence Cryo-EM structure determination of NLGN2 and NLGN3 ectodomains with structural comparison

    PMID:36479216

    Open questions at the time
    • Functional consequence of distinct protomer rotation not experimentally tested
    • Full-length structure including transmembrane and cytoplasmic domains lacking
  10. 2023 High

    The global 3D conformation of the MDGA1 ectodomain—not just its binding interface—is required for functional suppression of NLGN2: extended MDGA1 conformations fail to conceal NLGN2 from neurexin despite retaining binding affinity in solution.

    Evidence MDGA1 elbow mutagenesis; negative-stain EM conformational analysis; cell-binding and synaptogenesis assays

    PMID:36889589

    Open questions at the time
    • How MDGA1 conformation is regulated in vivo unknown
    • Whether other MDGA family members use similar conformational gating unresolved
  11. 2024 High

    Genetic epistasis confirmed functional antagonism between MDGA1 and NLGN2 in vivo: MDGA1 KO rescued gephyrin aggregation, inhibitory transmission deficits, and anxiety in Nlgn2 KO mice; NLGN2 also functions outside the nervous system at tight junctions in pancreatic acinar cells, where its loss disrupts the PALS1/PATJ polarity complex and activates YAP during neoplasia.

    Evidence Double-KO (Nlgn2×MDGA1) with electrophysiology and gephyrin imaging; NLGN2 immunolocalization and Co-IP of PALS1/PATJ in pancreatic tissue with YAP activity assays

    PMID:38413734 PMID:38571813 PMID:39284869

    Open questions at the time
    • Whether MDGA1-NLGN2 antagonism operates at all inhibitory synapse subtypes untested
    • Mechanism of NLGN2 interaction with PALS1/PATJ at tight junctions not structurally resolved
  12. 2025 High

    Domain-swap experiments definitively established that the NLGN2 extracellular domain is both necessary and sufficient for inhibitory-synapse targeting, while its cytoplasmic tail (including gephyrin-binding motif) is uniquely required for inhibitory but not excitatory synaptic function; in the lateral habenula, disrupting MDGA1–NLGN2 binding increases inhibitory synapse density and confers stress resilience.

    Evidence Chimeric Nlgn1-Nlgn2 rescue in neuroligin-null neurons with electrophysiology; MDGA1 KO and Nlgn2 MDGA1-binding-deficient knock-in in LHb with electrophysiology and chronic stress behavioral paradigm

    PMID:39747663 PMID:39897557

    Open questions at the time
    • Identity of the extracellular determinant within the NLGN2 ECD that specifies inhibitory targeting not mapped to specific residues
    • Whether LHb MDGA1-NLGN2 axis is therapeutically targetable unknown
  13. 2026 High

    NLGN2–neurexin adhesion is specifically required during a brief consolidation window (~10 min post-induction) for inhibitory long-term potentiation at both SST and PV inputs onto CA1 pyramidal cells, during which NLGN2 and gephyrin are recruited to potentiated synapses; biophysically, the NLGN2 ectodomain shows intermediate homodimerization affinity among neuroligins.

    Evidence Temporally controlled neurolide-2 peptide application during whole-cell recordings with optogenetic isolation of SST/PV inputs; mass photometry of recombinant NLGN2 ECD

    PMID:41802868 PMID:42033941

    Open questions at the time
    • Signaling cascade linking neurexin binding to gephyrin recruitment during iLTP not identified
    • Whether dimerization equilibrium is regulated at synapses in vivo unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease mediating NMDA-triggered NLGN2 cleavage, the specific extracellular residues that confer inhibitory-synapse targeting, the structural basis of the NLGN2–gephyrin cytoplasmic interaction, and whether the non-neuronal functions (pancreatic polarity, vascular regulation) share molecular mechanisms with synaptic NLGN2 function.
  • Protease identity for activity-dependent NLGN2 cleavage unknown
  • No atomic-resolution structure of full-length NLGN2 including transmembrane and cytoplasmic domains
  • Relationship between neuronal and non-neuronal NLGN2 functions mechanistically unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 6 GO:0005198 structural molecule activity 4
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 9 R-HSA-1500931 Cell-Cell communication 6 R-HSA-162582 Signal Transduction 2
Partners
FMRPGPHNIGSF9BMDGA1NRXN1NRXN2SERTSNX27
Complex memberships
NLGN2–MDGA1 cis complexNLGN2–gephyrin postsynaptic scaffoldNLGN2–neurexin trans-synaptic complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 MDGA1 binds NLGN2 with nanomolar affinity through its Ig1-Ig2 domains, which sterically block the same neurexin-binding region on NLGN2, thereby competitively inhibiting formation of NLGN2-neurexin trans-synaptic bridges. Crystal structure of MDGA1 Ig1-Ig2 alone and in complex with NLGN2 dimer, site-directed mutagenesis confirming interaction interface, binding affinity measurements Neuron High 28641112
2011 The NLGN2 R215H missense mutation causes retention of NLGN2 protein in the endoplasmic reticulum, preventing transport to the cell membrane and abolishing its ability to induce GABAergic synaptogenesis. Immunocytochemistry (subcellular localization), electrophysiological recordings of GABAergic synaptic currents in neuron coculture assay with mutant vs. wild-type NLGN2 Human molecular genetics High 21551456
2016 NLGN2 function at inhibitory synapses requires its extracellular domain (which confers inhibitory-synapse specificity) and two distinct cytoplasmic tail domains: one gephyrin-dependent mechanism disrupted by the autism-associated R705 mutation, and one gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Chimeric and point-mutant NLGN2 constructs expressed in rat CA1 neurons; whole-cell electrophysiology measuring inhibitory synaptic transmission eLife High 27805570
2025 The extracellular domain of NLGN2 determines its exclusive localization to inhibitory synapses (versus excitatory), while the cytoplasmic sequence of NLGN2—including its gephyrin-binding motif—is essential for its synaptic function at inhibitory synapses but dispensable for the excitatory-synapse function of NLGN1, revealing distinct intracellular mechanisms despite shared binding motifs. Chimeric Nlgn1-Nlgn2 constructs expressed in cultured hippocampal neurons lacking all neuroligins; whole-cell electrophysiology rescue experiments; synaptic localization imaging EMBO reports High 39747663
2019 Neuroligin-2, when internalized to endosomes, interacts directly with the PDZ domain of SNX27 via its PDZ-binding motif, enabling SNX27-mediated membrane recycling that maintains synaptic NLGN2 clusters, stabilizes synaptic GABAA receptors, and sustains inhibitory synapse strength. Co-immunoprecipitation, co-localization imaging, SNX27 knockdown/overexpression with measurement of inhibitory synapse markers and inhibitory synaptic currents Cell reports High 31775031
2011 Truncating mutations in NRXN2 fail to bind NLGN2 in cell binding assays and fail to promote synaptic differentiation in neuron coculture, establishing that the NRXN2–NLGN2 interaction is required for neurexin-mediated synaptogenic activity. Cell binding assays (NLGN2 binding to truncated NRXN2), neuron coculture synaptogenesis assay Human genetics Medium 21424692
2016 NLGN2 is localized to the majority of inhibitory (perisomatic) synapses in the basal amygdala; its deletion selectively impairs postsynaptic structure at perisomatic inhibitory synapses and reduces inhibitory synaptic transmission, leading to excessive activation of CaMKII-positive projection neurons under anxiogenic conditions. Immunohistochemistry, whole-cell electrophysiology of inhibitory transmission in Nlgn2 KO mice, cFOS activation assay with anxiogenic stimulus Neuropharmacology High 26142252
2015 Conditional knockout of Nlgn2 in adult medial prefrontal cortex causes major reductions in synaptic inhibition (but not immediately—only after 6-7 weeks), impairs behavioral stimulation of immediate-early gene expression in mPFC, and produces parallel cognitive and social behavioral impairments, demonstrating that NLGN2 is required for continuous maintenance of inhibitory synapses in the adult mPFC. Conditional KO (cKO) mice with stereotaxic viral Cre delivery; electrophysiology, immunostaining, behavioral battery, immediate-early gene expression Molecular psychiatry High 25824299
2018 NLGN2 physically associates with the serotonin transporter (SERT) in mouse midbrain in a calcium-independent (cis) interaction; loss of NLGN2 reduces midbrain and hippocampal SERT expression and function, decreases GABAA receptor-mediated IPSCs, and increases 5-HT1A autoreceptor sensitivity in dorsal raphe neurons. Proteomic analysis of SERT complexes, reciprocal co-immunoprecipitation, Western blot, dual-color in situ hybridization, immunocytochemistry, electrophysiology in Nlgn2 null mice Frontiers in synaptic neuroscience High 26793096
2018 NLGN2 R215H knock-in mice show a significant loss of NL2 protein in vivo, reduced GABAergic transmission, and impaired hippocampal activation, recapitulating schizophrenia-like behaviors, confirming that the single point mutation causes loss-of-function at inhibitory synapses in vivo. Transgenic knock-in mouse model; Western blot, electrophysiology, behavioral battery, immunostaining Molecular brain High 29859117
2018 Deletion of IgSF9b normalizes anxiety-related behaviors in Nlgn2 KO mice through differential effects at inhibitory synapses in the basal versus centromedial amygdala, placing IgSF9b downstream of or in a parallel pathway to NLGN2 in amygdala inhibitory circuit regulation; local IgSF9b deletion in CeM of Nlgn2 KO mice produces anxiolysis, establishing an epistatic relationship. Genetic epistasis (double KO), local viral KD in CeM, electrophysiology, behavioral assays, in vivo neural activity recordings Nature communications High 30573727
2018 NLGN2 overexpression in hippocampal neurons increases membrane localization of GABAergic postsynaptic proteins gephyrin and GABAARγ2, and the presynaptic marker VGAT, and increases parvalbumin-positive synaptic boutons co-localized with gephyrin, without affecting glutamatergic synaptic markers, demonstrating NLGN2 selectively drives trans-synaptic enhancement of GABAergic synapses. AAV-mediated NLGN2 overexpression in mouse hippocampus; immunofluorescence quantification of pre- and postsynaptic GABAergic and glutamatergic markers, behavioral battery Behavioural brain research Medium 30605713
2018 FMRP associates with Nlgn2 mRNA and suppresses its local synaptic translation; in Fmr1 KO mice, elevated NLGN2 mRNA translation occurs at synapses; additionally, NLGN2 protein levels at synapses are rapidly reduced by proteolytic cleavage following NMDA receptor stimulation. RNA immunoprecipitation (RIP) in synaptoneurosomes, synaptic translation assay, Western blot of synaptic fractions in Fmr1 KO mice, NMDA receptor stimulation cleavage assay Molecular neurobiology Medium 30056576
2019 In iPSC-derived cortical interneurons from schizophrenia patients, NLGN2 levels are reduced; NLGN2 overexpression rescues synaptic puncta deficits, while NLGN2 knockdown in healthy neurons reduces synaptic puncta density, establishing NLGN2 as a causal regulator of GABAergic synaptic connectivity in human cortical interneurons. iPSC-derived interneuron model; NLGN2 overexpression and knockdown; immunostaining of synaptic puncta density, action potential recordings Translational psychiatry Medium 31780643
2023 MDGA1 designer mutants that shift MDGA1 from compact to extended 3D conformations—without altering MDGA1-NLGN2 binding affinity in solution—nonetheless reduce cellular NLGN2 binding, decrease MDGA1's capacity to conceal NLGN2 from NRXN1β, and suppress NLGN2-mediated inhibitory presynaptic differentiation, demonstrating that the global 3D conformation of the MDGA1 ectodomain (not just the Ig1-Ig2 binding site) is required for its functional regulation of NLGN2. Designer mutagenesis at MDGA1 molecular elbows; negative-stain EM for conformation analysis; cell-binding assays; inhibitory synaptogenesis assay The Journal of biological chemistry High 36889589
2024 Loss of MDGA1 (but not heterozygous deletion of MDGA2) in hippocampal CA1 ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission, and the anxiety behavior characterizing Nlgn2 KO mice; combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta, establishing a functional antagonism between MDGA1 and NLGN2 at inhibitory synapses. Genetic double-KO (Nlgn2 KO × MDGA1 KO); electrophysiology, immunostaining of gephyrin puncta, behavioral anxiety tests Communications biology High 39284869
2025 MDGA1 and NLGN2 selectively interact in the lateral habenula (LHb); germline MDGA1 KO or introduction of an Nlgn2 variant incapable of binding MDGA1 increases inhibitory synaptic transmission and GABAergic synapse density in the LHb and confers resistance to chronic stress-induced depressive behaviors, demonstrating that MDGA1-mediated suppression of NLGN2 limits GABAergic synapse formation and facilitates depression. Transgenic conditional KO/knockin mouse models with viral Cre; electrophysiology, immunostaining, behavioral depression tests (chronic restraint stress paradigm), chemogenetic LH stimulation Theranostics High 39897557
2014 α-Dystroglycan binds both LNS2 and LNS6 domains of α-Nrxn1 via LARGE-dependent glycans, and its binding at LNS2 sterically prevents NLGN2 binding at LNS6, revealing that αDAG and NLGN2 compete for the same presynaptic α-neurexin molecule, providing a mechanism for regulating inhibitory synapse identity. Site-directed mutagenesis of Nrxn1α binding domains; cell-based binding competition assays; glycan manipulation The Journal of biological chemistry Medium 25157101
2013 Intra-hippocampal administration of neurolide-2 (a synthetic peptide spanning the NLGN2 neurexin-binding sequence) reduces sociability and increases aggression in rats, functionally linking hippocampal NLGN2–neurexin interaction to social behavior regulation. Stereotaxic intra-hippocampal peptide injection (neurolide-2); behavioral tests (sociability, aggression); Western blot and immunohistochemistry confirming endogenous NLGN2 reduction with chronic stress Neuropsychopharmacology Medium 24213355
2016 In hyperalgesic priming (a model of chronic pain), nlgn2 expression in the spinal dorsal horn increases via upregulation of the nlgn2A splice variant that promotes inhibitory synaptogenesis; disruption of nlgn2 function with neurolide-2 reverses the switch in GABAergic pharmacology polarity associated with chronic pain maintenance. Western blot and RT-PCR of nlgn2 splice variants; intra-spinal neurolide-2 peptide injection; behavioral pain assays Pain Medium 26859820
2018 NLGN2 knockdown in dopamine D1-positive NAc neurons promotes stress susceptibility and subordination, whereas NLGN2 knockdown in dopamine D2-positive NAc neurons mediates active defensive behavior, establishing a cell-type-specific role for NLGN2 in stress and depression-related circuitry. Cell-type-specific viral KD (Cre-dependent shRNA in D1-Cre and D2-Cre mice); chronic social defeat stress; behavioral battery Proceedings of the National Academy of Sciences High 29339486
2024 NLGN2 localizes to tight junctions in pancreatic acinar cells; loss of NLGN2 in pancreatic intraepithelial neoplasia disrupts the PALS1/PATJ polarity complex, thereby releasing YAP from contact inhibition and driving PanIN progression. Immunolocalization of NLGN2 in acinar cells and PanINs; co-immunoprecipitation of PALS1/PATJ complex; YAP activity assays; NLGN2 loss-of-function in PanIN model EMBO reports Medium 38413734
2019 HIV-1 Tat protein induces astrocytes to release extracellular vesicles containing miR-7, which is taken up by neurons and downregulates neuronal NLGN2 expression, leading to synaptic alterations that are reversible by PDGF-CC pretreatment. Astrocyte-neuron co-culture; EV isolation and miR-7 quantification; neuronal NLGN2 knockdown measured by Western blot; synaptic marker imaging; PDGF-CC rescue Journal of neuroimmune pharmacology Medium 31401755
2024 IgSF21 and NLGN2 regulate GABAergic presynaptic differentiation via distinct subcellular compartments and distinct downstream signaling: both require JNK-mediated signaling for synaptogenic activity, but NLGN2 additionally requires CaMKII and Src kinase activity while IgSF21 does not. Pharmacological inhibition of JNK, CaMKII, and Src kinase during synaptogenesis assay; monitoring presynaptic differentiation induced by IgSF21 vs. NLGN2 in vitro Frontiers in molecular neuroscience Medium 38571813
2013 Regulatory sequences in the 5' region and exon 1 of NLGN2 act as promoter elements with transcriptional activity that differs between neuronal and non-neuronal cell lines; two CpG-rich elements show distinct methylation and MeCP2 binding, identifying NLGN2 transcriptional regulation as dependent on and independent of MeCP2. Reporter gene assays in heterologous and neuronal cell lines; methylation analysis; MeCP2 binding assays Journal of neurochemistry Medium 23875667
2026 Nlgn2-neurexin adhesion is required for the consolidation (but not induction) of inhibitory long-term potentiation (iLTP) at both somatostatin and parvalbumin inputs onto hippocampal CA1 pyramidal cells; disruption of this interaction during a brief 10-min post-induction window blocks gephyrin clustering and NLGN2 recruitment to GABAergic synapses during iLTP. Whole-cell recordings in hippocampal slices; neurolide-2 peptide blocking of Nlgn2-neurexin binding; temporally controlled peptide application; optogenetics to isolate SST and PV inputs; immunostaining of gephyrin and NLGN2 clusters The Journal of neuroscience High 41802868
2022 The extracellular domain of human NLGN2, determined by cryo-EM, forms a homodimer with a distinct protomer rotation compared to NLGN3, which may differentially affect NLGN2 interactions with MDGAs. Cryo-electron microscopy structure determination of human NLGN2 and NLGN3; structural comparison with NLGN2-MDGA1 complex Frontiers in endocrinology Medium 36479216
2026 The extracellular domain (ECD) of NLGN2 exists in a concentration-dependent equilibrium between monomeric and dimeric forms, with NLGN2 having intermediate homodimerization affinity between NLGN3 (highest) and NLGN1 (lowest), as revealed by mass photometry. Mass photometry of recombinant human NLGN1, NLGN2, NLGN3 ECDs at nM concentrations; size exclusion chromatography-MALS as comparator Biochemical and biophysical research communications Medium 42033941
2018 In endothelial cells, NLGN2 co-localizes with collybistin (a CDC42 guanine nucleotide exchange factor also expressed in endothelial cells) and modulates Angiopoietin-2 release by regulating Weibel-Palade body exocytosis; NLGN2-null mice display immature vasculature with reduced pericyte coverage and reduced Tie2 phosphorylation. NLGN2 siRNA knockdown and overexpression in endothelial cells; co-immunoprecipitation with collybistin; measurement of Ang2 in conditioned medium; retina and tumor xenograft vascular analysis in Nlgn2-null mice Biochemical and biophysical research communications Medium 29709479

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human genetics 224 21424692
2013 Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Human molecular genetics 119 23393157
2005 Analysis of four neuroligin genes as candidates for autism. European journal of human genetics : EJHG 113 16077734
2011 Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Human molecular genetics 106 21551456
2012 Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. Behavioural brain research 102 22820233
2015 Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments. Molecular psychiatry 95 25824299
2009 Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience 81 19607885
2020 Tauopathy in the young autistic brain: novel biomarker and therapeutic target. Translational psychiatry 77 32661233
2016 Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. American journal of medical genetics. Part A 70 27865048
2016 Social Plasticity Relies on Different Neuroplasticity Mechanisms across the Brain Social Decision-Making Network in Zebrafish. Frontiers in behavioral neuroscience 65 26909029
2017 Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. Neuron 61 28641112
2013 Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 61 24213355
2020 Neuroligin-2 as a central organizer of inhibitory synapses in health and disease. Science signaling 60 33443230
2014 Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. The Journal of biological chemistry 58 25157101
2018 Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proceedings of the National Academy of Sciences of the United States of America 57 29339486
2019 Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. Translational psychiatry 54 31780643
2015 Neuroligin 2 deletion alters inhibitory synapse function and anxiety-associated neuronal activation in the amygdala. Neuropharmacology 51 26142252
2019 HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 49 31401755
2013 Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. PloS one 47 23451101
2016 Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses. eLife 43 27805570
2023 GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia. Biological psychiatry 34 37004850
2022 Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants. Genome medicine 34 35468861
2018 Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage. Molecular neurobiology 34 30056576
2017 NLGN1 and NLGN2 in the prefrontal cortex: their role in memory consolidation and strengthening. Current opinion in neurobiology 34 29278843
2015 Neuroligin-2 Expression in the Prefrontal Cortex is Involved in Attention Deficits Induced by Peripubertal Stress. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 28 26152839
2016 Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain. Pain 27 26859820
2020 The plasma peptides of sepsis. Clinical proteomics 26 32636717
2017 Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory. Frontiers in psychiatry 26 29230184
2020 PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex. Neuropharmacology 25 32818520
2024 Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization. The journal of headache and pain 24 38867170
2016 Whole-genome expression analysis reveals genes associated with treatment response to escitalopram in major depression. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 24 27461515
2019 SNX27-Mediated Recycling of Neuroligin-2 Regulates Inhibitory Signaling. Cell reports 23 31775031
2018 GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Molecular brain 23 29859117
2018 IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses. Nature communications 22 30573727
2018 The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice. Molecular brain 21 30231918
2013 Promoter-like sequences regulating transcriptional activity in neurexin and neuroligin genes. Journal of neurochemistry 20 23875667
2012 790 Kb microduplication in chromosome band 17p13.1 associated with intellectual disability, afebrile seizures, dysmorphic features, diabetes, and hypothyroidism. European journal of medical genetics 20 22365944
2023 Analyzing schizophrenia-related phenotypes in mice caused by autoantibodies against NRXN1α in schizophrenia. Brain, behavior, and immunity 16 37004758
2015 Practical Experience of the Application of a Weighted Burden Test to Whole Exome Sequence Data for Obesity and Schizophrenia. Annals of human genetics 16 26474449
2010 Differential expression of neuroligin genes in the nervous system of zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 16 20063411
2021 Altered theta and beta oscillatory synchrony in a genetic mouse model of pathological anxiety. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 33960026
2020 The effect of background strain on the behavioral phenotypes of the MDGA2+/- mouse model of autism spectrum disorder. Genes, brain, and behavior 13 32808443
2020 Altered expression of genes regulating inflammation and synaptogenesis during regrowth of afferent neurons to cochlear hair cells. PloS one 12 33001981
2018 Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors. Behavioural brain research 12 30605713
2016 Physical Interactions and Functional Relationships of Neuroligin 2 and Midbrain Serotonin Transporters. Frontiers in synaptic neuroscience 12 26793096
2014 Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome. American journal of medical genetics. Part A 12 25123844
2015 Developmental expression of the neuroligins and neurexins in fragile X mice. The Journal of comparative neurology 11 26235839
2024 Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism. Cerebral cortex (New York, N.Y. : 1991) 10 38696595
2023 Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function. The Journal of biological chemistry 10 36889589
2016 Hippocampal and motor fronto-cortical neuroligin1 is increased in an animal model of depression. Psychiatry research 10 27423632
2024 Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation. Communications biology 8 39284869
2023 Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3 Mice. Biomolecules 8 37509099
2022 Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders. Frontiers in endocrinology 8 36479216
2021 Proteomics Study on the Cerebrospinal Fluid of Patients with Encephalitis. ACS omega 8 34235299
2018 Modulation of Angiopoietin 2 release from endothelial cells and angiogenesis by the synaptic protein Neuroligin 2. Biochemical and biophysical research communications 8 29709479
2025 Chronic stress induces depression through MDGA1-Neuroligin2 mediated suppression of inhibitory synapses in the lateral habenula. Theranostics 7 39897557
2022 Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry. EBioMedicine 7 34990894
2022 Repeated Winning and Losing Experiences in Chronic Social Conflicts Are Linked to RNA Editing Pattern Difference. Frontiers in psychiatry 6 35664469
2025 Licochalcone A prevents cognitive decline in a lipopolysaccharide-induced neuroinflammation mice model. Molecular medicine (Cambridge, Mass.) 5 39930360
2024 Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization. Frontiers in molecular neuroscience 5 38571813
2024 Curcumin analog C16 attenuates bone cancer pain induced by MADB 106 breast cancer cells in female rats and inhibits the CREB/NLGN2 signaling axis by targeting CaMKⅠα. Neuropharmacology 5 39725125
2024 Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice. Molecular autism 4 38570872
2023 Expression alteration of Neuroligin family gene in attention deficit and hyperactivity disorder and autism spectrum disorder. Research in developmental disabilities 4 37285744
2013 Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer's Disease and Type 2 Diabetes Mellitus. Aging and disease 4 23936743
2025 Distinct mechanisms control the specific synaptic functions of Neuroligin 1 and Neuroligin 2. EMBO reports 3 39747663
2025 Analysis of neurexin-neuroligin complexes supports an isoform-specific role for beta-neurexin-1 dysfunction in a mouse model of autism. Molecular brain 3 40087687
2024 Establishment of transgenic fluorescent mice for labeling synapses and screening synaptogenic adhesion molecules. eLife 3 38450720
2024 Genetic Markers of Spina Bifida in an Indian Cohort. Journal of Indian Association of Pediatric Surgeons 3 39479418
2022 The differentially expressed proteins related to clinical viral encephalitis revealed by proteomics. Ibrain 3 37786892
2024 Alterations in Neuroligin-2 and BDNF proteins associated with anxiety-like behavior in salicylate-induced tinnitus rats. IBRO neuroscience reports 2 39624824
2020 [Co-expression of glutamatergic and autism-related genes in the hippocampus of male mice with disturbances of social behavior]. Vavilovskii zhurnal genetiki i selektsii 2 33659799
2012 Exploring the role of BCHE in the onset of Diabetes, Obesity and Neurological Disorders. Bioinformation 2 22493536
2025 Genetic Markers of Spina Bifida: Enrichment of Pathogenic Variants and Variants of Uncertain Significance. Journal of Indian Association of Pediatric Surgeons 1 40191489
2024 A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia. EMBO reports 1 38413734
2024 Paving the way to a neural fate - RNA signatures in naive and trans-differentiating mesenchymal stem cells. European journal of cell biology 1 39341198
2026 Neuroligin-2-Dependent Adhesion Defines a Molecular Checkpoint for Inhibitory Synaptic Plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 0 41802868
2026 The E3 Ubiquitin Ligase UBE3B Regulates Synaptic Development and Cortical Network Activity. Autism research : official journal of the International Society for Autism Research 0 41844341
2026 Ethanol Alters the Neurexin Landscape in Human Neuroblastoma Cells. Alcohol, clinical & experimental research 0 41968596
2026 Attack repertoires in outbred male CD1-mice are associated with nucleus accumbens neuroligin-2. eNeuro 0 42031556
2026 Mass photometry analysis revealed monomer-dimer equilibrium of the synaptic adhesion molecule neuroligin. Biochemical and biophysical research communications 0 42033941
2025 Neuroanatomical characterization of the cell adhesion molecule IgSF9b reveals localization to inhibitory and excitatory synapses in the mouse limbic system. Journal of molecular medicine (Berlin, Germany) 0 41105221
2025 Alogliptin Reduces Oxidative Stress in Cardiomyocytes and Ameliorates Diabetic Cardiomyopathy via the AURKB/NLGN2 Signaling. The Kaohsiung journal of medical sciences 0 41428503