{"gene":"NLGN1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2019,"finding":"PKA phosphorylates NLGN1 on S839, near the PDZ ligand, and this phosphorylation dynamically regulates binding to PSD-95. A phosphomimetic mutation (S839E) significantly reduced PSD-95 binding. Disruption of the NLGN1/PSD-95 interaction decreased surface expression of NLGN1 in cultured neurons and diminished NLGN1-mediated synaptic enhancement.","method":"Phosphomimetic mutagenesis, surface expression assays in cultured neurons, Co-IP, synaptic function assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis combined with multiple orthogonal methods (Co-IP, surface expression, functional synaptic assays) in a single focused study on this protein","pmids":["31138690"],"is_preprint":false},{"year":2012,"finding":"Human NLGN1 functions postsynaptically and can rescue behavioral deficits (osmotic avoidance and gentle touch response) in C. elegans nlg-1 mutants. Autism-associated point mutations R453C (equivalent to NLGN3 R451C) and truncation D432X (equivalent to NLGN4 D396X) introduced into human NLGN1 abolished rescue, establishing these residues as functionally critical. RNAi and transgenic rescue experiments confirmed a postsynaptic in vivo function of neuroligin in both muscle cells and neurons.","method":"Transgenic rescue in C. elegans nlg-1 mutants, RNAi feeding experiments, site-directed mutagenesis, behavioral assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue with mutagenesis in a model organism system, multiple behavioral readouts, single lab","pmids":["22723984"],"is_preprint":false},{"year":2009,"finding":"C. elegans nrx-1 and nlg-1 (orthologues of human NRXN1 and NLGN1) are required for correct synaptic function; mutants defective in nlg-1 show impaired osmotic avoidance behavior, confirmed by RNAi, demonstrating a synaptic role for neuroligin-1 at the organismal level.","method":"Loss-of-function mutant behavioral assays (osmotic avoidance), RNAi","journal":"Journal of visualized experiments : JoVE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with behavioral phenotype confirmed by RNAi in model organism, but single lab and limited mechanistic resolution","pmids":["20010541"],"is_preprint":false},{"year":2023,"finding":"Elevated mTORC1-driven cap-dependent translation in Tsc2 heterozygous mice increases NLGN1 mRNA translation and protein expression. Genetic or pharmacological inhibition of Nlgn1 expression rescued impaired hippocampal mGluR-LTD, contextual discrimination deficits, and social behavior deficits in Tsc2 mice without correcting mTORC1 hyperactivation, placing NLGN1 downstream of mTORC1 in this pathway.","method":"Genetic knockdown and pharmacological inhibition of Nlgn1 in Tsc2 mouse model, mGluR-LTD electrophysiology, behavioral assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic placement via genetic and pharmacological intervention with multiple orthogonal phenotypic readouts (LTD, behavior), single lab","pmids":["37293130"],"is_preprint":false},{"year":2025,"finding":"NRXN3 forms a complex with NLGN1 in the hippocampus. Downregulation of both NRXN3 and NLGN1 preceded synaptic plasticity alterations (reduced dendritic branch and spine lengths) and depression-related behaviors in a maternal separation rat model, identifying the NRXN3-NLGN1 complex as a mediator of stress-induced synaptic plasticity changes.","method":"Rat maternal separation model, protein expression analysis, dendritic morphology assays, behavioral assays","journal":"Brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative downregulation data with behavioral readout, no direct binding assay or mutagenesis reported in abstract, single lab","pmids":["40286836"],"is_preprint":false},{"year":2025,"finding":"MDGA2 interacts with Nlgn1; loss-of-function MDGA2 variants disrupt this interaction and perturb MDGA2-mediated synaptic functions, as demonstrated in mammalian expression systems and hippocampal cultured neurons. This places NLGN1 as a binding partner of MDGA2 in glutamatergic synapse regulation.","method":"Mammalian expression systems, hippocampal cultured neurons, functional studies of MDGA2 nonsense variants, interaction assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, NLGN1 is a secondary finding in a study focused on MDGA2, interaction disruption inferred from abstract without detailed method description","pmids":[],"is_preprint":true}],"current_model":"NLGN1 is a postsynaptic cell adhesion molecule that binds presynaptic neurexins (including the NRXN3-NLGN1 transsynaptic complex) and the scaffolding protein PSD-95; PKA-mediated phosphorylation of NLGN1 at S839 near its PDZ ligand dynamically regulates PSD-95 binding and thereby controls NLGN1 surface trafficking to synapses and synaptic enhancement, while NLGN1 protein levels are regulated downstream of mTORC1-driven cap-dependent translation, placing NLGN1 as a critical effector of excitatory synapse assembly and plasticity."},"narrative":{"mechanistic_narrative":"NLGN1 is a postsynaptic cell adhesion molecule that organizes excitatory synapse assembly and plasticity by linking presynaptic and postsynaptic compartments [PMID:22723984, PMID:20010541]. Its postsynaptic function is conserved and physiologically required: human NLGN1 rescues synaptic behavioral deficits in C. elegans nlg-1 mutants, and autism-associated mutations (R453C, D432X) abolish this rescue, defining residues critical for function [PMID:22723984, PMID:20010541]. PKA phosphorylates NLGN1 at S839 near its PDZ ligand, and this modification dynamically tunes binding to the scaffold PSD-95; disrupting the NLGN1/PSD-95 interaction reduces NLGN1 surface expression and diminishes NLGN1-mediated synaptic enhancement, coupling phosphorylation state to synaptic trafficking [PMID:31138690]. NLGN1 abundance is also set translationally downstream of mTORC1: elevated cap-dependent translation in Tsc2 heterozygous mice raises NLGN1, and lowering NLGN1 rescues mGluR-LTD and behavioral deficits, placing it as an effector limb of mTORC1 signaling [PMID:37293130].","teleology":[{"year":2009,"claim":"Established that neuroligin-1 is required for synaptic function at the organismal level, moving it from a candidate adhesion molecule to a functionally necessary synaptic component.","evidence":"Loss-of-function and RNAi behavioral assays (osmotic avoidance) in C. elegans nlg-1 mutants","pmids":["20010541"],"confidence":"Medium","gaps":["No molecular partners or postsynaptic mechanism resolved","Phenotype is behavioral, not synapse-resolved"]},{"year":2012,"claim":"Demonstrated that human NLGN1 acts postsynaptically and that specific disease-associated residues are functionally essential, by showing cross-species rescue and its loss with point/truncation mutations.","evidence":"Transgenic rescue and RNAi in C. elegans, site-directed mutagenesis, behavioral assays","pmids":["22723984"],"confidence":"Medium","gaps":["Mechanism by which R453C/D432X abolish function not defined","Mammalian validation of rescue not addressed"]},{"year":2019,"claim":"Identified a phosphoregulatory switch—PKA phosphorylation at S839—that controls NLGN1/PSD-95 binding and thereby surface trafficking and synaptic strength, explaining how NLGN1 function is dynamically gated.","evidence":"Phosphomimetic mutagenesis, Co-IP, surface expression and synaptic function assays in cultured neurons","pmids":["31138690"],"confidence":"High","gaps":["Kinase/phosphatase regulation in vivo not established","Whether phosphorylation responds to defined activity signals unknown"]},{"year":2023,"claim":"Placed NLGN1 downstream of mTORC1 by showing that translational upregulation of NLGN1 drives disease-relevant synaptic and behavioral deficits that are rescued by lowering NLGN1.","evidence":"Genetic knockdown and pharmacological inhibition of Nlgn1 in Tsc2 mice, mGluR-LTD electrophysiology, behavioral assays","pmids":["37293130"],"confidence":"Medium","gaps":["Direct link between NLGN1 levels and LTD machinery not defined","Single model system"]},{"year":2025,"claim":"Implicated the NRXN3-NLGN1 transsynaptic complex and the MDGA2-NLGN1 interaction as additional regulators of glutamatergic synapse structure and stress-related plasticity.","evidence":"Maternal separation rat model with expression and dendritic morphology analysis (NRXN3); mammalian expression systems and hippocampal neurons with MDGA2 variant interaction assays (preprint)","pmids":["40286836"],"confidence":"Low","gaps":["NRXN3-NLGN1 finding is correlative without direct binding/mutagenesis","MDGA2 interaction reported in a preprint as a secondary finding without detailed methods"]},{"year":null,"claim":"How phosphoregulation, transsynaptic neurexin binding, MDGA2 competition, and mTORC1-driven abundance are integrated to set excitatory synapse number and strength in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified in vivo model connecting trafficking control to translational control","Structural basis of partner selectivity not addressed in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":["NRXN3-NLGN1 transsynaptic complex"],"partners":["NRXN3","DLG4","MDGA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N2Q7","full_name":"Neuroligin-1","aliases":[],"length_aa":863,"mass_kda":96.4,"function":"Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and probably mediates its effects by recruiting and clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Required to maintain wakefulness quality and normal synchrony of cerebral cortex activity during wakefulness and sleep (By similarity). The protein is involved in nervous system development","subcellular_location":"Cell membrane; Postsynaptic density; Synaptic cleft; Synaptic cell membrane; Cell projection, dendrite; Synapse","url":"https://www.uniprot.org/uniprotkb/Q8N2Q7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NLGN1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NLGN1","total_profiled":1310},"omim":[{"mim_id":"618830","title":"AUTISM, SUSCEPTIBILITY TO, 20; AUTS20","url":"https://www.omim.org/entry/618830"},{"mim_id":"615697","title":"EPILEPSY, FAMILIAL TEMPORAL LOBE, 6; ETL6","url":"https://www.omim.org/entry/615697"},{"mim_id":"610868","title":"LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN 2; LRRTM2","url":"https://www.omim.org/entry/610868"},{"mim_id":"606479","title":"NEUROLIGIN 2; NLGN2","url":"https://www.omim.org/entry/606479"},{"mim_id":"606382","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 2; MAGI2","url":"https://www.omim.org/entry/606382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":11.9},{"tissue":"retina","ntpm":10.2}],"url":"https://www.proteinatlas.org/search/NLGN1"},"hgnc":{"alias_symbol":["KIAA1070","NLG1"],"prev_symbol":[]},"alphafold":{"accession":"Q8N2Q7","domains":[{"cath_id":"3.40.50.1820","chopping":"45-175_210-443_501-568","consensus_level":"medium","plddt":93.1241,"start":45,"end":568}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2Q7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2Q7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2Q7-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NLGN1","jax_strain_url":"https://www.jax.org/strain/search?query=NLGN1"},"sequence":{"accession":"Q8N2Q7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N2Q7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N2Q7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2Q7"}},"corpus_meta":[{"pmid":"31138690","id":"PMC_31138690","title":"PSD-95 binding dynamically regulates NLGN1 trafficking and function.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31138690","citation_count":52,"is_preprint":false},{"pmid":"27219346","id":"PMC_27219346","title":"Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.","date":"2016","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27219346","citation_count":51,"is_preprint":false},{"pmid":"26674772","id":"PMC_26674772","title":"Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26674772","citation_count":36,"is_preprint":false},{"pmid":"29278843","id":"PMC_29278843","title":"NLGN1 and NLGN2 in the prefrontal cortex: their role in memory consolidation and strengthening.","date":"2017","source":"Current opinion in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29278843","citation_count":34,"is_preprint":false},{"pmid":"22723984","id":"PMC_22723984","title":"Functional phenotypic rescue of Caenorhabditis elegans neuroligin-deficient mutants by the human and rat NLGN1 genes.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22723984","citation_count":23,"is_preprint":false},{"pmid":"20010541","id":"PMC_20010541","title":"Osmotic avoidance in Caenorhabditis elegans: synaptic function of two genes, orthologues of human NRXN1 and NLGN1, as candidates for autism.","date":"2009","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/20010541","citation_count":22,"is_preprint":false},{"pmid":"37293130","id":"PMC_37293130","title":"Reversal of memory and autism-related phenotypes in Tsc2 mice via inhibition of Nlgn1.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37293130","citation_count":6,"is_preprint":false},{"pmid":"36170021","id":"PMC_36170021","title":"A regulatory circuit of lncRNA NLGN1-AS1 and Wnt signalling controls clear cell renal cell carcinoma phenotypes through FZD4-modulated pathways.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36170021","citation_count":3,"is_preprint":false},{"pmid":"40286836","id":"PMC_40286836","title":"NRXN3-NLGN1 complex influences the development of depression induced by maternal separation in rats.","date":"2025","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/40286836","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.12.669930","title":"Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use","date":"2025-08-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.12.669930","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.03.621787","title":"Molecular Signatures of Resilience to Alzheimer’s Disease in Neocortical Layer 4 Neurons","date":"2024-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.03.621787","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.28.25330873","title":"<i>MDGA2</i> homozygous loss-of-function variants cause developmental and epileptic encephalopathy","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.25330873","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.30.615737","title":"Change in brain molecular landscapes following electrical stimulation of the nucleus accumbens","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.30.615737","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8752,"output_tokens":1725,"usd":0.026065,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8507,"output_tokens":2014,"usd":0.046442,"stage2_stop_reason":"end_turn"},"total_usd":0.072507,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PKA phosphorylates NLGN1 on S839, near the PDZ ligand, and this phosphorylation dynamically regulates binding to PSD-95. A phosphomimetic mutation (S839E) significantly reduced PSD-95 binding. Disruption of the NLGN1/PSD-95 interaction decreased surface expression of NLGN1 in cultured neurons and diminished NLGN1-mediated synaptic enhancement.\",\n      \"method\": \"Phosphomimetic mutagenesis, surface expression assays in cultured neurons, Co-IP, synaptic function assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis combined with multiple orthogonal methods (Co-IP, surface expression, functional synaptic assays) in a single focused study on this protein\",\n      \"pmids\": [\"31138690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human NLGN1 functions postsynaptically and can rescue behavioral deficits (osmotic avoidance and gentle touch response) in C. elegans nlg-1 mutants. Autism-associated point mutations R453C (equivalent to NLGN3 R451C) and truncation D432X (equivalent to NLGN4 D396X) introduced into human NLGN1 abolished rescue, establishing these residues as functionally critical. RNAi and transgenic rescue experiments confirmed a postsynaptic in vivo function of neuroligin in both muscle cells and neurons.\",\n      \"method\": \"Transgenic rescue in C. elegans nlg-1 mutants, RNAi feeding experiments, site-directed mutagenesis, behavioral assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue with mutagenesis in a model organism system, multiple behavioral readouts, single lab\",\n      \"pmids\": [\"22723984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans nrx-1 and nlg-1 (orthologues of human NRXN1 and NLGN1) are required for correct synaptic function; mutants defective in nlg-1 show impaired osmotic avoidance behavior, confirmed by RNAi, demonstrating a synaptic role for neuroligin-1 at the organismal level.\",\n      \"method\": \"Loss-of-function mutant behavioral assays (osmotic avoidance), RNAi\",\n      \"journal\": \"Journal of visualized experiments : JoVE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with behavioral phenotype confirmed by RNAi in model organism, but single lab and limited mechanistic resolution\",\n      \"pmids\": [\"20010541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elevated mTORC1-driven cap-dependent translation in Tsc2 heterozygous mice increases NLGN1 mRNA translation and protein expression. Genetic or pharmacological inhibition of Nlgn1 expression rescued impaired hippocampal mGluR-LTD, contextual discrimination deficits, and social behavior deficits in Tsc2 mice without correcting mTORC1 hyperactivation, placing NLGN1 downstream of mTORC1 in this pathway.\",\n      \"method\": \"Genetic knockdown and pharmacological inhibition of Nlgn1 in Tsc2 mouse model, mGluR-LTD electrophysiology, behavioral assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic placement via genetic and pharmacological intervention with multiple orthogonal phenotypic readouts (LTD, behavior), single lab\",\n      \"pmids\": [\"37293130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRXN3 forms a complex with NLGN1 in the hippocampus. Downregulation of both NRXN3 and NLGN1 preceded synaptic plasticity alterations (reduced dendritic branch and spine lengths) and depression-related behaviors in a maternal separation rat model, identifying the NRXN3-NLGN1 complex as a mediator of stress-induced synaptic plasticity changes.\",\n      \"method\": \"Rat maternal separation model, protein expression analysis, dendritic morphology assays, behavioral assays\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative downregulation data with behavioral readout, no direct binding assay or mutagenesis reported in abstract, single lab\",\n      \"pmids\": [\"40286836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA2 interacts with Nlgn1; loss-of-function MDGA2 variants disrupt this interaction and perturb MDGA2-mediated synaptic functions, as demonstrated in mammalian expression systems and hippocampal cultured neurons. This places NLGN1 as a binding partner of MDGA2 in glutamatergic synapse regulation.\",\n      \"method\": \"Mammalian expression systems, hippocampal cultured neurons, functional studies of MDGA2 nonsense variants, interaction assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, NLGN1 is a secondary finding in a study focused on MDGA2, interaction disruption inferred from abstract without detailed method description\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NLGN1 is a postsynaptic cell adhesion molecule that binds presynaptic neurexins (including the NRXN3-NLGN1 transsynaptic complex) and the scaffolding protein PSD-95; PKA-mediated phosphorylation of NLGN1 at S839 near its PDZ ligand dynamically regulates PSD-95 binding and thereby controls NLGN1 surface trafficking to synapses and synaptic enhancement, while NLGN1 protein levels are regulated downstream of mTORC1-driven cap-dependent translation, placing NLGN1 as a critical effector of excitatory synapse assembly and plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NLGN1 is a postsynaptic cell adhesion molecule that organizes excitatory synapse assembly and plasticity by linking presynaptic and postsynaptic compartments [#1, #2]. Its postsynaptic function is conserved and physiologically required: human NLGN1 rescues synaptic behavioral deficits in C. elegans nlg-1 mutants, and autism-associated mutations (R453C, D432X) abolish this rescue, defining residues critical for function [#1, #2]. PKA phosphorylates NLGN1 at S839 near its PDZ ligand, and this modification dynamically tunes binding to the scaffold PSD-95; disrupting the NLGN1/PSD-95 interaction reduces NLGN1 surface expression and diminishes NLGN1-mediated synaptic enhancement, coupling phosphorylation state to synaptic trafficking [#0]. NLGN1 abundance is also set translationally downstream of mTORC1: elevated cap-dependent translation in Tsc2 heterozygous mice raises NLGN1, and lowering NLGN1 rescues mGluR-LTD and behavioral deficits, placing it as an effector limb of mTORC1 signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that neuroligin-1 is required for synaptic function at the organismal level, moving it from a candidate adhesion molecule to a functionally necessary synaptic component.\",\n      \"evidence\": \"Loss-of-function and RNAi behavioral assays (osmotic avoidance) in C. elegans nlg-1 mutants\",\n      \"pmids\": [\"20010541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partners or postsynaptic mechanism resolved\", \"Phenotype is behavioral, not synapse-resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that human NLGN1 acts postsynaptically and that specific disease-associated residues are functionally essential, by showing cross-species rescue and its loss with point/truncation mutations.\",\n      \"evidence\": \"Transgenic rescue and RNAi in C. elegans, site-directed mutagenesis, behavioral assays\",\n      \"pmids\": [\"22723984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which R453C/D432X abolish function not defined\", \"Mammalian validation of rescue not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a phosphoregulatory switch—PKA phosphorylation at S839—that controls NLGN1/PSD-95 binding and thereby surface trafficking and synaptic strength, explaining how NLGN1 function is dynamically gated.\",\n      \"evidence\": \"Phosphomimetic mutagenesis, Co-IP, surface expression and synaptic function assays in cultured neurons\",\n      \"pmids\": [\"31138690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase regulation in vivo not established\", \"Whether phosphorylation responds to defined activity signals unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed NLGN1 downstream of mTORC1 by showing that translational upregulation of NLGN1 drives disease-relevant synaptic and behavioral deficits that are rescued by lowering NLGN1.\",\n      \"evidence\": \"Genetic knockdown and pharmacological inhibition of Nlgn1 in Tsc2 mice, mGluR-LTD electrophysiology, behavioral assays\",\n      \"pmids\": [\"37293130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between NLGN1 levels and LTD machinery not defined\", \"Single model system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated the NRXN3-NLGN1 transsynaptic complex and the MDGA2-NLGN1 interaction as additional regulators of glutamatergic synapse structure and stress-related plasticity.\",\n      \"evidence\": \"Maternal separation rat model with expression and dendritic morphology analysis (NRXN3); mammalian expression systems and hippocampal neurons with MDGA2 variant interaction assays (preprint)\",\n      \"pmids\": [\"40286836\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NRXN3-NLGN1 finding is correlative without direct binding/mutagenesis\", \"MDGA2 interaction reported in a preprint as a secondary finding without detailed methods\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How phosphoregulation, transsynaptic neurexin binding, MDGA2 competition, and mTORC1-driven abundance are integrated to set excitatory synapse number and strength in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified in vivo model connecting trafficking control to translational control\", \"Structural basis of partner selectivity not addressed in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0112316\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"NRXN3-NLGN1 transsynaptic complex\"],\n    \"partners\": [\"NRXN3\", \"DLG4\", \"MDGA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}