Affinage

NLGN2

Neuroligin-2 · UniProt Q8NFZ4

Length
835 aa
Mass
90.8 kDa
Annotated
2026-06-10
83 papers in source corpus 30 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLGN2 is a postsynaptic cell-adhesion molecule that organizes GABAergic inhibitory synapses by forming trans-synaptic bridges with presynaptic neurexins, and its abundance directly sets inhibitory synapse number and signaling strength (PMID:31780643, PMID:30605713). Its extracellular domain confers inhibitory-synapse specificity while its cytoplasmic tail is indispensable for function, acting through two intracellular routes: a gephyrin-dependent arm (disrupted by the autism-associated R705 mutation) and a gephyrin-independent arm requiring the S714 phosphorylation site (PMID:27805570); the gephyrin-binding motif is essential for NLGN2 but, despite identical sequence, dispensable for NLGN1 at excitatory synapses, indicating isoform-specific intracellular wiring (PMID:39747663). The neurexin bridge is competitively and conformationally regulated in cis: MDGA1 Ig1-Ig2 spans the NLGN2 dimer and sterically blocks the neurexin-binding surface, with MDGA1's global ectodomain conformation determining its inhibitory effect (PMID:28641112, PMID:36889589), and α-dystroglycan competes with NLGN2 for α-neurexin (PMID:25157101). Neurexin engagement itself is ligand-selective, with β-Nrxn1 recruited by NLGN2 and modulated by the AS4 splice insert (PMID:40087687). Surface NLGN2 levels are maintained by SNX27-mediated endosomal recycling via a PDZ interaction, which tunes inhibitory synapse composition (PMID:31775031), and its expression is set by FMRP-dependent repression of local translation together with NMDA-induced proteolytic cleavage (PMID:30056576). Functionally, NLGN2-neurexin adhesion drives gephyrin clustering required for inhibitory LTP consolidation in CA1 (PMID:41802868), and loss of NLGN2 reduces inhibitory transmission across prefrontal cortex, amygdala, raphe, and other circuits, producing anxiety, cognitive, social, and stress-related behavioral deficits (PMID:25824299, PMID:26142252, PMID:29339486); the R215H mutation abolishes protein expression and recapitulates GABAergic and behavioral pathology in vivo (PMID:21551456, PMID:29859117). Beyond neurons, NLGN2 controls Angiopoietin-2 secretion from endothelial Weibel-Palade bodies (PMID:29709479) and supports epithelial contact inhibition through assembly of the PALS1/PATJ polarity complex that restrains YAP (PMID:38413734).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2011 Medium

    Established that a specific missense mutation disrupts NLGN2 trafficking and that the NRXN2-NLGN2 interaction is required for synaptic differentiation, linking molecular adhesion to GABAergic synaptogenesis.

    Evidence R215H ER-retention assay by ICC/electrophysiology, and NRXN2 truncation binding/coculture assays

    PMID:21424692 PMID:21551456

    Open questions at the time
    • Did not resolve the in vivo behavioral consequence of trafficking loss
    • Single-lab cell-based assays without structural detail of the binding interface
  2. 2013 Medium

    Showed that bidirectionally manipulating hippocampal NLGN2 shifts excitation/inhibition balance and social/emotional behavior, connecting synaptic adhesion to circuit-level behavior.

    Evidence AAV overexpression and neurolide-2 peptide disruption in rat hippocampus with GAD65/protein quantification and behavioral tests

    PMID:23451101 PMID:24213355

    Open questions at the time
    • Peptide and overexpression effects are correlative for endogenous synapse dynamics
    • Circuit specificity not dissected
  3. 2014 Medium

    Identified α-dystroglycan as a competitor for α-neurexin binding, revealing that NLGN2's trans-synaptic bridge is regulated by competition at the neurexin surface.

    Evidence Site-directed mutagenesis and binding/glycan assays mapping LNS2/LNS6 binding

    PMID:25157101

    Open questions at the time
    • Competition shown biochemically but not at native synapses
    • Functional consequence for inhibitory synapse density untested
  4. 2015 High

    Demonstrated that NLGN2 is continuously required to maintain inhibitory synapses in adult brain, establishing an ongoing rather than purely developmental role.

    Evidence Adult conditional/regional Nlgn2 KO in mPFC and amygdala with electrophysiology, IHC, cFOS, and behavior

    PMID:25824299 PMID:26142252

    Open questions at the time
    • Did not identify the maintenance signaling pathway
    • Cell-type specificity within each region only partially resolved
  5. 2016 High

    Dissected the extracellular versus intracellular contributions, defining inhibitory-synapse specificity in the ectodomain and two separable cytoplasmic arms (gephyrin-dependent R705, gephyrin-independent S714).

    Evidence Chimeric construct rescue and mutagenesis with CA1 electrophysiology; also showed NLGN3 depends on NLGN2

    PMID:27805570

    Open questions at the time
    • S714 phosphorylation site is putative; the kinase and gephyrin-independent effector were not identified
    • Did not establish the SERT-NLGN2 complex stoichiometry described separately
  6. 2016 High

    Extended NLGN2 function beyond classic inhibitory synapses to somatodendritic complexes with the serotonin transporter, linking NLGN2 to serotonergic raphe physiology.

    Evidence Reciprocal Co-IP, ISH, ICC, and electrophysiology in Nlgn2 null mice

    PMID:26793096

    Open questions at the time
    • Mechanism by which NLGN2 stabilizes SERT is undefined
    • Direct versus indirect nature of the SERT complex unresolved
  7. 2017 High

    Provided the structural basis for cis-regulation, showing MDGA1 sterically occludes the neurexin-binding region of the NLGN2 dimer.

    Evidence Crystal structure of MDGA1 Ig1-Ig2 bound to NLGN2 dimer with mutagenesis and affinity measurements

    PMID:28641112

    Open questions at the time
    • Did not establish in vivo MDGA1 stoichiometry or regulation
    • Conformational requirements addressed only later
  8. 2018 Medium

    Identified post-transcriptional and post-translational control of NLGN2 levels through FMRP-repressed local translation and NMDA-triggered cleavage, and confirmed the R215H mutation causes loss of protein and pathology in vivo.

    Evidence RNA-IP/synaptoneurosome translation assays, NMDA cleavage western blots, and R215H knock-in mouse phenotyping

    PMID:29859117 PMID:30056576

    Open questions at the time
    • Protease responsible for NMDA-induced cleavage not identified
    • Functional impact of cleavage on synapse stability not quantified
  9. 2018 High

    Placed NLGN2 within defined circuit and genetic frameworks, identifying IgSF9b as an epistatic modifier in amygdala and cell-type-specific NAc roles in stress behavior.

    Evidence Nlgn2/IgSF9b double KO and D1/D2 cell-type-specific viral knockdown with electrophysiology and behavior

    PMID:29339486 PMID:30573727

    Open questions at the time
    • Molecular interaction between NLGN2 and IgSF9b not established
    • How cell-type identity dictates opposite behavioral outcomes unresolved
  10. 2018 Medium

    Revealed a non-neuronal endothelial role, where NLGN2 controls Angiopoietin-2 release from Weibel-Palade bodies and vascular maturation.

    Evidence siRNA/overexpression Ang2 secretion assays and Nlgn2 null vascular analysis with collybistin co-localization

    PMID:29709479

    Open questions at the time
    • Mechanism coupling NLGN2 to Weibel-Palade body exocytosis unknown
    • Whether collybistin mediates the endothelial function untested
  11. 2019 High

    Established surface-level maintenance via SNX27-mediated endosomal recycling and showed NLGN2 dosage directly sets inhibitory synapse number in human neurons.

    Evidence Co-IP/knockdown of SNX27 with electrophysiology, and NLGN2 OE/KD in iPSC-derived interneurons with puncta quantification

    PMID:31775031 PMID:31780643

    Open questions at the time
    • Signals triggering NLGN2 endocytosis versus recycling not defined
    • Link between recycling and activity-dependent plasticity untested
  12. 2019 Low

    Identified an indirect regulatory route in which astrocyte-derived EV miR-7 downregulates neuronal NLGN2 under HIV-1 Tat exposure.

    Evidence Astrocyte EV isolation, miR-7 quantification, and neuronal NLGN2/synaptic measurement

    PMID:31401755

    Open questions at the time
    • No direct NLGN2 rescue experiment confirming causality
    • Single-lab, indirect mechanism with NLGN2 only as downstream target
  13. 2020 Medium

    Positioned NLGN2 in a compensatory homeostatic pathway whereby excitatory scaffold loss upregulates and traffics NLGN2 to strengthen inhibition.

    Evidence PSD-95 heterozygous mice with electrophysiology, western blot, and trafficking assays

    PMID:32818520

    Open questions at the time
    • Signal coupling PSD-95 loss to NLGN2 trafficking not identified
    • Whether this is direct or circuit-mediated unresolved
  14. 2022 Medium

    Provided full-length dimer architecture, showing isoform-specific protomer rotations that could underlie differential MDGA regulation.

    Evidence Cryo-EM structures of human NLGN2 and NLGN3 homodimers with structural comparison

    PMID:36479216

    Open questions at the time
    • Functional consequence of the rotational difference not validated
    • Link to MDGA selectivity remains structural inference
  15. 2023 High

    Showed that MDGA1's global 3D conformation, not just its interaction interface, governs its ability to suppress NLGN2-mediated presynaptic differentiation.

    Evidence Crystal structure plus elbow mutants with cell-based binding and presynaptic differentiation assays

    PMID:36889589

    Open questions at the time
    • Physiological trigger that alters MDGA1 conformation unknown
    • In vivo relevance of conformational regulation untested
  16. 2024 High

    Defined NLGN2's mechanistic role in inhibitory plasticity and its distinct intracellular signaling requirements, and extended its biology to pancreatic epithelial polarity.

    Evidence Neurolide-2/optogenetics iLTP assays in CA1, kinase-inhibitor synaptogenesis assays, and pancreatic acinar KO with PALS1/PATJ-YAP readouts

    PMID:38413734 PMID:38571813 PMID:41802868

    Open questions at the time
    • How CaMKII/Src/JNK signaling converges on NLGN2 synaptogenic output is unclear
    • Mechanism linking NLGN2 to PALS1/PATJ assembly at tight junctions undefined
  17. 2024 High

    Resolved MDGA1 as a genetic modifier of NLGN2 in vivo and clarified the divergence between NLGN2 and NLGN1 intracellular mechanisms despite shared gephyrin motifs.

    Evidence Nlgn2/MDGA1 double KO with electrophysiology/IHC/behavior; chimeric rescue in neuroligin-deficient neurons

    PMID:39284869 PMID:39747663

    Open questions at the time
    • The effector distinguishing identical gephyrin motifs in NLGN1 versus NLGN2 not identified
    • Layer-specific gephyrin loss mechanism unresolved
  18. 2025 Medium

    Refined ligand selectivity and demonstrated a stress-regulated NLGN2-MDGA1 interaction in the lateral habenula controlling depression susceptibility.

    Evidence Transcellular neurexin recruitment assays with AS4 splice analysis; LHb conditional KO and NLGN2 binding-deficient knock-in with electrophysiology and behavior

    PMID:39897557 PMID:40087687

    Open questions at the time
    • How chronic stress increases NLGN2-MDGA1 binding mechanistically is unknown
    • Whether AS4-modulated selectivity operates at native synapses untested
  19. 2026 Medium

    Quantified isoform-specific homodimerization, showing NLGN2 occupies an intermediate monomer-dimer equilibrium relative to NLGN1 and NLGN3.

    Evidence Mass photometry and SEC-MALS of recombinant NLGN2 ectodomain

    PMID:42033941

    Open questions at the time
    • Functional consequence of the dimerization equilibrium not established
    • No link to in vivo synaptic clustering demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The effectors that distinguish the identical NLGN1/NLGN2 gephyrin-binding motifs, the gephyrin-independent S714 pathway, and the protease and physiological control of NMDA-induced NLGN2 cleavage remain undefined.
  • No kinase or downstream effector identified for the S714 gephyrin-independent arm
  • Protease mediating NLGN2 cleavage unknown
  • Mechanism converting shared gephyrin motif into isoform-specific function unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1500931 Cell-Cell communication 3
Partners
DAG1FMR1GPHNMDGA1NRXN1NRXN2SLC6A4SNX27
Complex memberships
PALS1/PATJ polarity complexgephyrin postsynaptic scaffold

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 MDGA1 Ig1-Ig2 binds NLGN2 with nanomolar affinity; crystal structures show two MDGA1 Ig1-Ig2 molecules each spanning the entire NLGN2 dimer, with Ig1 binding the same region on NLGN2 as neurexins do, thereby sterically blocking neurexin access to NLGN2 and regulating trans-synaptic bridge formation. Crystal structure determination, site-directed mutagenesis, binding affinity measurements Neuron High 28641112
2011 The NLGN2 R215H missense mutation causes retention of the protein in the endoplasmic reticulum and prevents transport to the cell membrane, resulting in loss-of-function for GABAergic synaptogenesis as measured by immunocytochemistry and electrophysiological recordings. Immunocytochemistry, electrophysiological recordings, in vitro cell-based functional assay Human molecular genetics Medium 21551456
2011 Truncating mutations in NRXN2 fail to bind NLGN2 in cell binding assays, establishing that the NRXN2-NLGN2 interaction is required for synaptic differentiation in neuron coculture. Cell binding assay, neuron coculture synaptogenesis assay Human genetics Medium 21424692
2016 The extracellular domain of NLGN2 confers inhibitory synapse specificity, while the cytoplasmic tail is indispensable for function; two intracellular domains were identified: one gephyrin-dependent (disrupted by autism-associated R705 mutation) and one gephyrin-independent (reliant on putative phosphorylation site S714). Chimeric construct expression, electrophysiology in rat CA1 hippocampal neurons, site-directed mutagenesis eLife High 27805570
2019 NLGN2 is recycled from endosomes back to the plasma membrane via direct interaction between the PDZ domain of SNX27 and the PDZ-binding motif of NLGN2; SNX27-mediated recycling enhances synaptic NLGN2 clusters and affects inhibitory synapse composition and GABAergic signaling strength. Co-localization, co-immunoprecipitation, knockdown experiments, electrophysiology Cell reports High 31775031
2018 FMRP associates with Nlgn2 mRNA in synaptoneurosomes and neuronal cultures and represses its local synaptic translation; in Fmr1 KO mice, elevated NLGN2 translation occurs. Additionally, NLGN2 undergoes rapid proteolytic cleavage upon NMDA receptor stimulation in both wild-type and Fmr1 KO mice. RNA immunoprecipitation, synaptoneurosomes fractionation, NMDA stimulation assays, western blot Molecular neurobiology Medium 30056576
2016 NLGN3 function at inhibitory synapses depends on the presence of NLGN2, and a domain in the extracellular region of NLGN2 accounts for the functional difference between NLGN2 and NLGN3 at inhibitory synapses. Chimeric construct expression, electrophysiology in rat hippocampal CA1 neurons eLife High 27805570
2015 Conditional knockout of Nlgn2 in adult medial prefrontal cortex causes major reductions in synaptic inhibition after 6-7 weeks and impairs anxiety, fear memory, and social interaction behaviors; Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC. Conditional knockout mouse, electrophysiology, behavioral tests, immediate-early gene expression assay Molecular psychiatry High 25824299
2015 Nlgn2 deletion predominantly affects inhibitory synapses at perisomatic sites in the basal amygdala, impairs inhibitory synaptic transmission, and leads to excessive activation of CaMKII-positive projection neurons (but not parvalbumin- or somatostatin-positive interneurons) under anxiogenic conditions. Knockout mouse, electrophysiology, immunohistochemistry, cFOS activation assay Neuropharmacology High 26142252
2018 Deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in Nlgn2 KO mice through differential effects at inhibitory synapses in basal versus centromedial amygdala, placing IgSF9b downstream of or parallel to Nlgn2 in amygdala inhibitory circuit regulation. Double knockout mouse, electrophysiology, behavioral tests, local region-specific viral KO Nature communications High 30573727
2016 NLGN2 in the midbrain forms Ca2+-independent complexes with serotonin transporter (SERT) in somatodendritic compartments of raphe neurons, co-localizing with α-neurexin and gephyrin; loss of NLGN2 reduces midbrain SERT expression and function, reduces GABAergic IPSCs onto dorsal raphe 5-HT neurons, and increases 5-HT1A autoreceptor sensitivity. Reciprocal co-immunoprecipitation, in situ hybridization, immunocytochemistry, electrophysiology in Nlgn2 null mice Frontiers in synaptic neuroscience High 26793096
2019 NLGN2 overexpression rescues synaptic puncta deficits in schizophrenia iPSC-derived cortical interneurons, while NLGN2 knockdown in healthy neurons reduces synaptic puncta density, demonstrating that NLGN2 levels directly regulate inhibitory synapse number in human cortical interneurons. iPSC-derived neurons, NLGN2 overexpression/knockdown, synaptic puncta quantification Translational psychiatry Medium 31780643
2018 Nlgn2 R215H knock-in mice express no detectable NL2 protein, show reduced GABAergic transmission, and display anxiety-like behavior, impaired prepulse inhibition, cognitive deficits, and abnormal stress responses, demonstrating that this single point mutation causes GABAergic synaptic and behavioral pathology in vivo. Knock-in mouse model, electrophysiology, behavioral battery Molecular brain Medium 29859117
2014 Dystroglycan (αDAG) binds both LNS2 and LNS6 domains of Nrxn1α, and its binding at LNS2 sterically prevents NLGN2 interaction at LNS6, establishing that αDAG and NLGN2 compete for binding to α-neurexin at inhibitory synapses. Site-directed mutagenesis, binding assays, glycan analysis The Journal of biological chemistry Medium 25157101
2018 AAV-mediated overexpression of NLGN2 in mouse hippocampus increases gephyrin and GABAARγ2 membrane localization and VGAT presynaptic protein levels (trans-synaptic enhancement), increases parvalbumin-positive synaptic boutons, and causes cognitive impairments in hippocampus-dependent tasks without altering glutamatergic markers. AAV overexpression, immunohistochemistry, behavioral tests Behavioural brain research Medium 30605713
2013 Intra-hippocampal administration of neurolide-2 (a synthetic peptide interfering with NLGN2-neurexin interaction) reduces sociability and increases aggression in rats, mimicking the social behavioral effects of chronic restraint stress that also reduces hippocampal NLGN2 protein levels. Intra-hippocampal peptide injection, western blot, immunohistochemistry, electron microscopy, behavioral tests Neuropsychopharmacology Medium 24213355
2013 AAV-mediated overexpression of NLGN2 in rat dorsal hippocampus increases GAD65 expression, reduces exploratory behavior toward novel stimuli, and decreases offensive aggression, indicating that hippocampal NLGN2 modulates the excitation/inhibition balance and social/emotional behavior. AAV overexpression in rat hippocampus, GAD65 immunohistochemistry, behavioral tests PloS one Medium 23451101
2024 NLGN2-neurexin adhesion is required for inhibitory long-term potentiation (iLTP) consolidation in hippocampal CA1 pyramidal cells; disruption with neurolide-2 blocks gephyrin clustering and NLGN2 recruitment to GABAergic synapses during NMDA-induced iLTP, with a critical 10-min post-induction window, and NMDA-induced iLTP at both SST and PV inputs depends on NLGN2. Synthetic peptide (neurolide-2) application, whole-cell recordings in hippocampal slices, immunostaining, optogenetics The Journal of neuroscience High 41802868
2025 NLGN2's extracellular domain determines inhibitory synapse specificity (exchangeable with NLGN1 extracellular domain to redirect function), while its cytoplasmic gephyrin-binding motif is essential for NLGN2 function at inhibitory synapses but dispensable for NLGN1 function at excitatory synapses, revealing distinct intracellular mechanisms for the two neuroligins despite identical gephyrin-binding motif sequences. Chimeric construct functional rescue in neuroligin-deficient hippocampal neurons, electrophysiology EMBO reports High 39747663
2023 MDGA1 designer mutants that alter the 3D conformation of the MDGA1 ectodomain (via strategic elbow mutations far from the MDGA1-NLGN2 interaction site) reduce cellular NLGN2 binding and NLGN2-mediated inhibitory presynaptic differentiation, even while leaving soluble ectodomain binding affinity intact, demonstrating that the global 3D conformation of MDGA1 is critical for regulating NLGN2 function. Crystal structure, site-directed mutagenesis, cell-based binding assays, inhibitory presynaptic differentiation assay The Journal of biological chemistry High 36889589
2025 In the lateral habenula, MDGA1 directly interacts with NLGN2 (interaction elevated by chronic restraint stress); loss of MDGA1 or introduction of an NLGN2 variant incapable of binding MDGA1 increases inhibitory synaptic transmission and GABAergic synapse density in the LHb, reduces stress-induced LHb hyperactivation, and confers resistance to depression-like behaviors. Conditional knockout mouse, knock-in mouse, electrophysiology, immunostaining, behavioral tests Theranostics High 39897557
2024 Loss of MDGA1 (but not heterozygous MDGA2 deletion) ameliorates abnormal cytosolic gephyrin aggregation, reduced inhibitory synaptic transmission, and exacerbated anxiety in Nlgn2 KO mice; combined Nlgn2 and MDGA1 deletion causes exacerbated layer-specific loss of gephyrin puncta, establishing MDGA1 as a functional modulator of NLGN2 in recruiting GABAergic postsynaptic gephyrin scaffold. Double knockout mouse, electrophysiology, immunohistochemistry, behavioral tests Communications biology High 39284869
2022 Cryo-EM structures of human NLGN2 and NLGN3 homodimers reveal relative rotations of the two protomers between isoforms, suggesting that distinct dimer assemblies may underlie differential interactions with MDGA regulators. Cryo-electron microscopy structure determination, structural comparison Frontiers in endocrinology Medium 36479216
2020 PSD-95 deficiency promotes inhibitory synapse function through upregulation and trafficking of NLGN2, placing NLGN2 downstream of PSD-95 in a pathway linking excitatory scaffold disruption to compensatory GABAergic inhibition. PSD-95 heterozygous transgenic mice, electrophysiology, western blot, protein trafficking assay Neuropharmacology Medium 32818520
2024 Nlgn2 synaptogenic activity at GABAergic synapses requires CaMKII and Src kinase signaling (in addition to JNK), whereas IgSF21-mediated GABAergic synaptogenesis requires only JNK, establishing a distinct intracellular signaling requirement for NLGN2-mediated inhibitory presynaptic differentiation. Pharmacological inhibition of kinase pathways, synaptogenesis assay in cultured neurons Frontiers in molecular neuroscience Medium 38571813
2024 In pancreatic acinar cells, NLGN2 localizes to tight junctions and is required for formation of the PALS1/PATJ polarity complex, which reduces YAP activity to maintain contact inhibition; NLGN2 is lost progressively from low- to high-grade pancreatic intraepithelial neoplasias. Immunolocalization, KO/knockdown experiments, PALS1/PATJ complex assessment, YAP activity assay EMBO reports Medium 38413734
2018 NLGN2 silencing in endothelial cells strongly reduces Angiopoietin 2 (Ang2) release upon VEGF stimulation and increases retention of Weibel-Palade bodies; NLGN2 overexpression depletes Weibel-Palade bodies; NLGN2 null mice show immature vasculature with lower pericyte coverage and reduced Tie2 phosphorylation; NLGN2 co-localizes with collybistin in endothelial cells. siRNA knockdown, NLGN2 overexpression, in vitro Ang2 secretion assay, NLGN2 null mouse in vivo vascular analysis, immunolocalization Biochemical and biophysical research communications Medium 29709479
2019 HIV-1 Tat exposure of astrocytes induces release of extracellular vesicles containing miR-7, which is taken up by neurons and downregulates neuronal NLGN2, leading to synaptic alterations that are reversed by PDGF-CC pretreatment. Astrocyte culture, extracellular vesicle isolation, miR-7 quantification, neuronal NLGN2 measurement, synaptic assay Journal of neuroimmune pharmacology Low 31401755
2026 Mass photometry revealed that recombinant human NLGN2 extracellular domain exists in a concentration-dependent monomer-dimer equilibrium at nanomolar concentrations, with NLGN2 showing intermediate homodimerization affinity compared to NLGN3 (highest) and NLGN1 (lowest), indicating isoform-specific dimer interface properties. Mass photometry, size exclusion chromatography-MALS Biochemical and biophysical research communications Medium 42033941
2025 Beta-Nrxn1 (but not alpha-Nrxn1) can be recruited to synaptic contacts by both GABAergic NLGN2 and glutamatergic NLGN1 in transcellular assays; insertion of alternative spliced segment 4 (AS4) negatively modulates presynaptic recruitment of Nrxn1 by neuroligins; an autism-associated mutant beta-Nrxn1 shows ligand restriction to glutamatergic NLGN1, losing interaction with NLGN2. Transcellular synaptic recruitment assay, neurexin isoform analysis in autism mouse model Molecular brain Medium 40087687
2018 Nlgn2 deletion in adult medial prefrontal cortex or knockdown selectively in dopamine D1-positive cells in nucleus accumbens promotes stress susceptibility, while knockdown in D2-positive cells mediates active defensive behavior, establishing cell-type-specific roles for NLGN2 in NAc circuits underlying depression and stress. Cell-type-specific viral knockdown, chronic social defeat stress, behavioral tests Proceedings of the National Academy of Sciences of the United States of America Medium 29339486

Source papers

Stage 0 corpus · 83 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 229 21424692
2013 Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Human molecular genetics 121 23393157
2005 Analysis of four neuroligin genes as candidates for autism. European journal of human genetics : EJHG 114 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 103 22820233
2015 Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments. Molecular psychiatry 96 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 71 27865048
2016 Social Plasticity Relies on Different Neuroplasticity Mechanisms across the Brain Social Decision-Making Network in Zebrafish. Frontiers in behavioral neuroscience 67 26909029
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 64 24213355
2020 Neuroligin-2 as a central organizer of inhibitory synapses in health and disease. Science signaling 62 33443230
2017 Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. Neuron 62 28641112
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 59 29339486
2014 Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. The Journal of biological chemistry 58 25157101
2019 Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. Translational psychiatry 55 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 50 31401755
2013 Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. PloS one 49 23451101
2016 Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses. eLife 43 27805570
2022 Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants. Genome medicine 36 35468861
2023 GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia. Biological psychiatry 34 37004850
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
2016 Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain. Pain 28 26859820
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
2020 PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex. Neuropharmacology 27 32818520
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
2024 Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization. The journal of headache and pain 25 38867170
2018 GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Molecular brain 24 29859117
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 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
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) 11 38696595
2023 Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function. The Journal of biological chemistry 11 36889589
2015 Developmental expression of the neuroligins and neurexins in fragile X mice. The Journal of comparative neurology 11 26235839
2016 Hippocampal and motor fronto-cortical neuroligin1 is increased in an animal model of depression. Psychiatry research 10 27423632
2025 Chronic stress induces depression through MDGA1-Neuroligin2 mediated suppression of inhibitory synapses in the lateral habenula. Theranostics 9 39897557
2024 Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation. Communications biology 9 39284869
2022 Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders. Frontiers in endocrinology 9 36479216
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 Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry. EBioMedicine 8 34990894
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 Licochalcone A prevents cognitive decline in a lipopolysaccharide-induced neuroinflammation mice model. Molecular medicine (Cambridge, Mass.) 7 39930360
2022 Repeated Winning and Losing Experiences in Chronic Social Conflicts Are Linked to RNA Editing Pattern Difference. Frontiers in psychiatry 6 35664469
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
2023 Expression alteration of Neuroligin family gene in attention deficit and hyperactivity disorder and autism spectrum disorder. Research in developmental disabilities 5 37285744
2025 Distinct mechanisms control the specific synaptic functions of Neuroligin 1 and Neuroligin 2. EMBO reports 4 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 4 40087687
2024 Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice. Molecular autism 4 38570872
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
2024 Establishment of transgenic fluorescent mice for labeling synapses and screening synaptogenic adhesion molecules. eLife 3 38450720
2024 Paving the way to a neural fate - RNA signatures in naive and trans-differentiating mesenchymal stem cells. European journal of cell biology 3 39341198
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
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
2026 Real-world-data for phenotypes and genotypes of rare monogenic genetic epilepsies and genes of uncertain significance for epilepsy. Epilepsia open 0 42220229
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

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