{"gene":"GRID1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2017,"finding":"GluD1 functions downstream of mGlu1 receptor to mediate slow depolarizing currents in midbrain dopamine neurons. In HEK cells co-expressing mGlu1 and GluD1, mGlu1 agonist elicits a slow depolarizing current absent in cells expressing either alone; a dominant-negative dead-pore GluD1 mutant abolishes both agonist-evoked and slow postsynaptic mGlu1-dependent currents in dopamine neurons from midbrain slices and in GRID1 knockout mice. In vivo, spontaneous burst firing of dopamine neurons is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant.","method":"HEK cell co-expression electrophysiology, dominant-negative mutant expression in midbrain slices, in vivo recordings in GRID1 knockout mice","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reconstitution in HEK cells, dominant-negative mutagenesis, native slice recordings, in vivo recordings, genetic knockout), converging on same conclusion","pmids":["28696429"],"is_preprint":false},{"year":2024,"finding":"A missense variant in the GluD1 distal amino-terminal domain at a position predicted to interact with Cbln2/Cbln4 disrupts complex formation between GluD1 and Cbln2 in biochemical assays. Additionally, the schizophrenia-associated M3 domain variant GluD1-A650T produces constitutively active receptor currents, analogous to the lurcher mutation in GluD2. Pentamidine potently inhibited constitutive currents of GluD receptor variants (GluD2-T649A IC50 ~50 nM).","method":"Electrophysiological assays, biochemical complex formation assays, mutagenesis of GRID1/GRID2 cDNA","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and electrophysiology in a single rigorous study with multiple orthogonal assays","pmids":["37944084"],"is_preprint":false},{"year":2024,"finding":"Homozygous missense GRID1 variants (p.Arg161His and p.Thr752Met) identified in patients with intellectual disability and spastic paraplegia impair mGlu1/5 metabotropic glutamate receptor signaling via Ca2+ and ERK pathways and impair dendrite morphology and excitatory synapse density in dissociated and organotypic slice culture neurons. Molecular modeling indicated these mutations alter the hinge between GluD1 cerebellin and D-serine binding domains. Expression, trafficking, physical interaction with mGlu1, and cerebellin binding were not conspicuously altered by these mutations.","method":"Molecular modeling, electrophysiological recordings, Ca2+ signaling assays, ERK pathway assays, neuronal culture morphological analysis in dissociated and organotypic slice cultures","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (structural modeling, electrophysiology, Ca2+ imaging, ERK biochemistry, morphological analysis) in a single study with human variant validation","pmids":["38418578"],"is_preprint":false},{"year":2012,"finding":"Deletion of GluD1 (GRID1 knockout mice) leads to hyperactivity, lower anxiety, depression-like behavior, aggression, and social interaction deficits. At the molecular level, synaptoneurosome preparations from GluD1 KO mice show lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2, and PSD95 expression in the amygdala, indicating GluD1 regulates postsynaptic AMPA receptor content in a region-specific manner. D-Cycloserine rescued social interaction deficits and normalized lower GluA1 expression in prefrontal cortex.","method":"GluD1 knockout mouse behavioral analysis, synaptoneurosome biochemical fractionation, pharmacological rescue experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular phenotype (synaptoneurosome fractionation) and pharmacological rescue across multiple behavioral readouts","pmids":["22412961"],"is_preprint":false},{"year":2015,"finding":"GluD1 knockout mice exhibit higher dendritic spine number, greater excitatory neurotransmission, higher synapse number, and abnormalities in LIMK1-cofilin signaling in the medial prefrontal cortex and CA1 hippocampus. A lower GluN2A/GluN2B expression ratio was also observed, indicating GluD1 is required for the developmental GluN2B-to-GluN2A NMDAR subunit switch. GluN2B-selective inhibitor Ro-25-6981 partially normalized LIMK1-cofilin signaling and reduced excess spine number.","method":"GluD1 knockout mouse spine counting, electrophysiology, western blotting, pharmacological rescue with GluN2B inhibitor","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple molecular readouts (spine morphology, electrophysiology, biochemistry) and pharmacological rescue, single lab","pmids":["25721396"],"is_preprint":false},{"year":2021,"finding":"GluD1 loss in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core leads to reduced inhibitory neurotransmission, evidenced by decreased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, increased paired pulse ratio of evoked inhibitory responses (indicating reduced presynaptic release probability), and reduced GAD67 puncta (inhibitory terminals). Local ablation of GluD1 from NAc caused hypolocomotion and altered anxiety- and depression-like behaviors, while ablation from dorsal striatum produced opposite behavioral phenotypes.","method":"Conditional GluD1 knockout, whole-cell patch clamp electrophysiology, paired pulse ratio analysis, GAD67 immunofluorescence, behavioral testing","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — region-specific conditional KO with electrophysiological and morphological readouts plus behavioral phenotyping, single lab","pmids":["34173171"],"is_preprint":false},{"year":2022,"finding":"Conditional deletion of GluD1 from excitatory neurons in corticolimbic regions leads to overactive Akt-mTOR pathway, higher p62, and lower LC3-II/LC3-I ratio in the somatosensory cortex, indicating reduced autophagy. Excitatory synaptic elements were increased in number but showed an immature phenotype with lower GluA1 expression and impaired GluN2B-to-GluN2A developmental switch. Overactive Akt-mTOR signaling and impaired autophagy were also observed in dorsal striatum, prefrontal cortex, and hippocampus.","method":"Conditional GluD1 knockout mouse, western blotting for Akt-mTOR pathway components and autophagy markers (p62, LC3), synaptic puncta analysis, behavioral testing","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic KO with multiple biochemical pathway readouts (Akt-mTOR, autophagy markers, receptor subunits), single lab","pmids":["35304260"],"is_preprint":false},{"year":2025,"finding":"GRID1/GluD1 directly facilitates autophagy and reduces AMPA receptor (AMPAR) expression in the central amygdala (CeA). Using a GRID1 C-terminal-derived peptide (Tat-HRSPN), GRID1 was shown to directly interact with autophagy mediators nGOPC/nPIST, BECN1, and LAMP1. During inflammatory and neuropathic pain, GRID1 and CBLN1 are downregulated in CeA alongside impaired autophagic flux and increased excitatory neurotransmission and AMPAR expression. GluD1 is preferentially expressed in PRKCD+ neurons of the CeA where BECN1 and LAMP1 co-localize.","method":"GRID1 C-terminal peptide (Tat-HRSPN) application, co-immunoprecipitation/interaction assays with BECN1/LAMP1/nGOPC, western blotting for autophagy markers, pain models (CFA inflammatory, spinal nerve ligation), electrophysiology for mEPSCs, immunofluorescence","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide-based functional intervention plus interaction assays and multiple biochemical/electrophysiological readouts, single lab","pmids":["41147487"],"is_preprint":false},{"year":2014,"finding":"GRID1 expression is downregulated in iPS cells derived from both MECP2-mutated and CDKL5-mutated Rett syndrome patients and upregulated during neuronal precursor and mature neuron differentiation, consistent with a role as a postsynaptic adhesion molecule that preferentially induces inhibitory presynaptic differentiation of cortical neurons.","method":"iPS cell gene expression profiling, real-time RT-PCR in CDKL5- and MECP2-mutated cells during neuronal differentiation","journal":"European journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression measurement in iPS cells, no direct functional manipulation of GluD1 protein, single method","pmids":["24916645"],"is_preprint":false},{"year":2025,"finding":"In rodents and non-human primates, GluD1 immunoreactivity in the lateral habenula (LHb) is primarily expressed in dendritic profiles and is strongly localized to the core of symmetric (GABAergic) synapses, with lower perisynaptic presence at asymmetric (glutamatergic) synapses. Axon terminals from the entopeduncular nucleus and lateral hypothalamus show postsynaptic GluD1 immunolabeling in LHb, as determined by anterograde tracing combined with immunogold labeling.","method":"Immunoelectron microscopy (pre- and post-embedding immunogold), anterograde tracing combined with immunogold labeling in rat and monkey tissue","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy with two orthogonal approaches (pre- and post-embedding) in two species","pmids":["39794140"],"is_preprint":false},{"year":2023,"finding":"The NRXN1-CBLN1-GluD1 transsynaptic complex at VMHvl-to-arcuate AgRP/NPY neuron excitatory synapses regulates aggression. Targeted deletion of GluD1 from arcuate AgRP neurons impairs excitatory synapses from VMHvl neurons onto AgRP/NPY neurons and increases aggression. Heterozygous deficiency of Grid1 synergizes with increased UBE3A to further increase aggression, placing GluD1 as a postsynaptic component of the NRXN1-CBLN1-GluD1 transsynaptic complex required for this hypothalamic circuit.","method":"Conditional Grid1 deletion in AgRP neurons, chemogenetic/optogenetic activation, behavioral aggression assays, epistasis with Nrxn1 and Ube3a genetic manipulations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic KO with circuit-level epistasis and multiple orthogonal manipulations (chemogenetics, optogenetics, genetics), preprint only","pmids":["36909588"],"is_preprint":true},{"year":2024,"finding":"Grid1 knockdown in hypothalamic neurons (via lentiviral vector) decreases Grid1 and Rfrp-3 mRNA expression but increases Gnrh mRNA. ICV injection of LV-Grid1 in prepubertal rats causes earlier vaginal opening, increased Gnrh mRNA, decreased Rfrp-3 mRNA, decreased progesterone concentration, and altered follicular development, indicating GluD1 modulates puberty onset via Gnrh and Rfrp-3 regulation in the hypothalamus.","method":"Lentiviral Grid1 knockdown in hypothalamic neurons, ICV injection in prepubertal female rats, qRT-PCR, hormone measurement (progesterone), histological ovary analysis","journal":"The Journal of veterinary medical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with mRNA/hormone readouts, no direct protein-level mechanistic validation","pmids":["38479882"],"is_preprint":false},{"year":2025,"finding":"HDAC5 inhibitor T2943 promotes H3K14 acetylation at the Grid1 promoter region, enhancing GRID1 transcription and expression. GRID1 knockdown blocks the antidepressant behavioral effect of T2943 in mice, establishing GRID1 as a downstream effector of HDAC5-dependent chromatin remodeling in the antidepressant response.","method":"CUT&Tag chromatin profiling, GRID1 knockdown, behavioral tests (forced swim, sucrose preference), HDAC5 inhibitor pharmacology","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, chromatin profiling plus KD rescue, mechanistic link between H3K14ac and GRID1 promoter inferred from CUT&Tag without direct promoter-reporter validation","pmids":["39915556"],"is_preprint":false}],"current_model":"GluD1 (GRID1) is a postsynaptic ionotropic glutamate receptor-family protein that functions primarily as a non-classical synaptogenic scaffold rather than a conventional ligand-gated ion channel: it forms a transsynaptic bridge via cerebellin (Cbln) family proteins and presynaptic neurexins, mediates slow depolarizing currents downstream of mGlu1 receptor activation in midbrain dopamine neurons (controlling burst firing), regulates the postsynaptic content of AMPA and NMDA receptor subunits and the GluN2B-to-GluN2A developmental switch, controls dendritic spine density and excitatory/inhibitory synapse balance in cortex, hippocampus, striatum, and nucleus accumbens through both pre- and postsynaptic mechanisms, and facilitates autophagic flux via direct interactions with BECN1, LAMP1, and nGOPC/nPIST; disease-associated missense variants disrupt its cerebellin-binding domain or D-serine-binding domain, impair mGlu1/5 signaling, and certain M3-domain variants create constitutively active channels."},"narrative":{"mechanistic_narrative":"GRID1 encodes GluD1, a glutamate receptor-family protein that functions principally as a postsynaptic organizer of excitatory and inhibitory synapses across multiple brain circuits rather than as a conventional ligand-gated channel [PMID:28696429, PMID:25721396]. In midbrain dopamine neurons GluD1 acts downstream of the mGlu1 receptor to generate slow depolarizing currents that drive spontaneous burst firing, an activity abolished by a dominant-negative dead-pore mutant or by Grid1 knockout [PMID:28696429]. At synapses GluD1 serves as the postsynaptic component of a NRXN1-CBLN1-GluD1 transsynaptic complex that specifies excitatory connectivity, as shown for VMHvl-to-AgRP/NPY hypothalamic synapses controlling aggression [PMID:36909588]. Loss of GluD1 dysregulates postsynaptic receptor composition in a region-specific manner — altering AMPA receptor subunit content, impairing the developmental GluN2B-to-GluN2A NMDAR switch, and perturbing LIMK1-cofilin signaling, dendritic spine density, and synapse number in cortex, hippocampus, striatum, and nucleus accumbens [PMID:22412961, PMID:25721396, PMID:34173171]. GluD1 additionally facilitates autophagic flux through direct interactions of its C-terminus with nGOPC/nPIST, BECN1, and LAMP1, and its loss produces overactive Akt-mTOR signaling and impaired autophagy alongside immature excitatory synapses [PMID:35304260, PMID:41147487]. Homozygous missense GRID1 variants cause intellectual disability with spastic paraplegia by altering the hinge between the cerebellin- and D-serine-binding domains and impairing mGlu1/5 signaling through Ca2+ and ERK pathways, while distinct variants disrupt cerebellin binding or create constitutively active channels [PMID:37944084, PMID:38418578].","teleology":[{"year":2012,"claim":"Established that GluD1 controls postsynaptic AMPA receptor content and behavior in a region-specific way, defining it as a synaptic regulator rather than a passive structural subunit.","evidence":"Grid1 knockout mouse behavior, synaptoneurosome fractionation, and D-cycloserine pharmacological rescue","pmids":["22412961"],"confidence":"Medium","gaps":["Did not resolve whether AMPAR changes are direct or secondary to circuit remodeling","No molecular mechanism linking GluD1 to receptor subunit trafficking"]},{"year":2015,"claim":"Showed GluD1 is required for the developmental GluN2B-to-GluN2A NMDAR switch and constrains dendritic spine number via LIMK1-cofilin signaling, connecting GluD1 to spine maturation.","evidence":"Grid1 knockout spine counting, electrophysiology, western blotting, and GluN2B-inhibitor rescue in mPFC and CA1","pmids":["25721396"],"confidence":"Medium","gaps":["Mechanism coupling GluD1 to LIMK1-cofilin not defined","Direct versus indirect control of NMDAR subunit composition unresolved"]},{"year":2017,"claim":"Answered how GluD1 contributes to signaling without classical gating: it acts downstream of mGlu1 to produce slow depolarizing currents driving dopamine neuron burst firing.","evidence":"HEK co-expression electrophysiology, dominant-negative dead-pore mutant in midbrain slices, and in vivo recordings in Grid1 knockout mice","pmids":["28696429"],"confidence":"High","gaps":["Structural basis of mGlu1-GluD1 coupling not determined","Whether ion flux through GluD1 itself or a downstream conductance carries the current"]},{"year":2021,"claim":"Extended GluD1 function to inhibitory transmission, showing region-specific loss reduces inhibitory synapse number and presynaptic release with opposing behavioral effects in NAc versus dorsal striatum.","evidence":"Conditional Grid1 knockout, patch clamp with paired-pulse analysis, GAD67 immunofluorescence, and behavioral testing","pmids":["34173171"],"confidence":"Medium","gaps":["Mechanism by which a postsynaptic protein lowers presynaptic release probability unclear","Transsynaptic partner mediating inhibitory effect not identified in this study"]},{"year":2022,"claim":"Linked GluD1 loss to overactive Akt-mTOR signaling and impaired autophagy accompanying immature excitatory synapses, introducing an autophagy axis to GluD1 biology.","evidence":"Conditional Grid1 knockout, western blotting for Akt-mTOR and autophagy markers (p62, LC3), and synaptic puncta analysis","pmids":["35304260"],"confidence":"Medium","gaps":["Did not establish direct molecular link between GluD1 and autophagy machinery","Causal direction between synapse immaturity and autophagy defect unresolved"]},{"year":2023,"claim":"Defined GluD1 as the postsynaptic component of a NRXN1-CBLN1-GluD1 transsynaptic complex specifying a hypothalamic excitatory circuit that regulates aggression.","evidence":"Conditional Grid1 deletion in AgRP neurons, chemogenetic/optogenetic manipulation, aggression assays, and epistasis with Nrxn1 and Ube3a (preprint)","pmids":["36909588"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Biochemical reconstitution of the tripartite complex not shown in this study"]},{"year":2024,"claim":"Connected GRID1 to human Mendelian disease, showing homozygous missense variants cause intellectual disability and spastic paraplegia by altering the cerebellin/D-serine domain hinge and impairing mGlu1/5 Ca2+ and ERK signaling.","evidence":"Patient variant identification, molecular modeling, electrophysiology, Ca2+ and ERK assays, and neuronal morphology in dissociated and slice cultures","pmids":["38418578"],"confidence":"High","gaps":["Variants did not conspicuously alter expression, trafficking, mGlu1 interaction, or cerebellin binding, leaving precise signaling lesion undefined","No in vivo model of the human variants"]},{"year":2024,"claim":"Resolved how distinct variant classes act, distinguishing cerebellin-binding-disrupting amino-terminal variants from M3-domain variants that produce constitutively active currents, with pentamidine identified as an inhibitor.","evidence":"Mutagenesis of GRID1/GRID2 cDNA, electrophysiology, and biochemical complex-formation assays","pmids":["37944084"],"confidence":"High","gaps":["In vivo consequences of constitutively active variants not tested","Therapeutic relevance of pentamidine inhibition not validated in disease models"]},{"year":2025,"claim":"Provided direct evidence that GluD1 physically engages autophagy machinery, with its C-terminus interacting with nGOPC/nPIST, BECN1, and LAMP1 to promote autophagy and limit AMPAR expression in central amygdala pain circuits.","evidence":"Tat-HRSPN C-terminal peptide intervention, interaction assays with BECN1/LAMP1/nGOPC, autophagy marker blotting, pain models, and mEPSC recordings","pmids":["41147487"],"confidence":"Medium","gaps":["Interaction assays from a single lab without reciprocal structural validation","Stoichiometry and regulation of the GluD1-autophagy interactions unknown"]},{"year":2025,"claim":"Defined the precise synaptic localization of GluD1, placing it at the core of symmetric (GABAergic) synapses in the lateral habenula, consistent with a role in organizing inhibitory contacts.","evidence":"Pre- and post-embedding immunogold electron microscopy with anterograde tracing in rat and monkey lateral habenula","pmids":["39794140"],"confidence":"Medium","gaps":["Functional consequence of GABAergic-synapse localization not tested here","Transsynaptic partners at these symmetric synapses not identified"]},{"year":null,"claim":"How GluD1's transsynaptic adhesion role, its mGlu1-coupled conductance, and its direct autophagy interactions are integrated into a single molecular mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying ligand-binding, channel, and C-terminal autophagy functions","Whether autophagy regulation and synaptic organization are coupled or independent activities","Causal mechanism by which a postsynaptic protein controls presynaptic release and inhibitory connectivity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[10,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":["NRXN1-CBLN1-GluD1 transsynaptic complex"],"partners":["CBLN1","CBLN2","NRXN1","GRM1","BECN1","LAMP1","GOPC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULK0","full_name":"Glutamate receptor ionotropic, delta-1","aliases":[],"length_aa":1009,"mass_kda":112.1,"function":"Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system. Although it shares structural features with ionotropic glutamate receptors, does not bind glutamate as a primary ligand (PubMed:38060673). Instead, forms trans-synaptic adhesion complexes with presynaptic neurexins and cerebellins, regulating NMDA and AMPA receptor activity and influencing synaptic plasticity through signal transduction (By similarity). In the presence of neurexins and cerebellins, forms cation-selective channels that are proposed to be gated by glycine and D-serine (By similarity). However, recent research disputes this ligand-gated cation channel activity (PubMed:39052831). Cation-selective ion channel can be triggered by GRM1 in dopaminergic neurons (By similarity). Also acts as a receptor for GABA, modulating inhibitory synaptic plasticity through non-ionotropic mechanisms (PubMed:38060673)","subcellular_location":"Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULK0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRID1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRID1","total_profiled":1310},"omim":[{"mim_id":"615029","title":"PRECEREBELLIN 4; CBLN4","url":"https://www.omim.org/entry/615029"},{"mim_id":"612242","title":"CHROMOSOME 10q22.3-q23.2 DELETION SYNDROME","url":"https://www.omim.org/entry/612242"},{"mim_id":"610659","title":"GLUTAMATE RECEPTOR, IONOTROPIC, DELTA 1; GRID1","url":"https://www.omim.org/entry/610659"},{"mim_id":"600433","title":"PRECEREBELLIN 2; CBLN2","url":"https://www.omim.org/entry/600433"},{"mim_id":"600432","title":"PRECEREBELLIN 1; CBLN1","url":"https://www.omim.org/entry/600432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":5.5}],"url":"https://www.proteinatlas.org/search/GRID1"},"hgnc":{"alias_symbol":["GluD1","KIAA1220"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULK0","domains":[{"cath_id":"3.40.50.2300","chopping":"24-146_293-383","consensus_level":"medium","plddt":82.6705,"start":24,"end":383},{"cath_id":"3.40.50.2300","chopping":"149-289_394-424","consensus_level":"medium","plddt":84.2624,"start":149,"end":424},{"cath_id":"3.40.190.10","chopping":"439-541_775-801","consensus_level":"high","plddt":89.5334,"start":439,"end":801},{"cath_id":"3.40.190.10","chopping":"544-551_662-766","consensus_level":"medium","plddt":82.8663,"start":544,"end":766},{"cath_id":"1.10.287,1.10.287","chopping":"557-658","consensus_level":"medium","plddt":80.1364,"start":557,"end":658}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULK0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULK0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULK0-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRID1","jax_strain_url":"https://www.jax.org/strain/search?query=GRID1"},"sequence":{"accession":"Q9ULK0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULK0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULK0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULK0"}},"corpus_meta":[{"pmid":"16380905","id":"PMC_16380905","title":"Bipolar 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In HEK cells co-expressing mGlu1 and GluD1, mGlu1 agonist elicits a slow depolarizing current absent in cells expressing either alone; a dominant-negative dead-pore GluD1 mutant abolishes both agonist-evoked and slow postsynaptic mGlu1-dependent currents in dopamine neurons from midbrain slices and in GRID1 knockout mice. In vivo, spontaneous burst firing of dopamine neurons is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant.\",\n      \"method\": \"HEK cell co-expression electrophysiology, dominant-negative mutant expression in midbrain slices, in vivo recordings in GRID1 knockout mice\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reconstitution in HEK cells, dominant-negative mutagenesis, native slice recordings, in vivo recordings, genetic knockout), converging on same conclusion\",\n      \"pmids\": [\"28696429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense variant in the GluD1 distal amino-terminal domain at a position predicted to interact with Cbln2/Cbln4 disrupts complex formation between GluD1 and Cbln2 in biochemical assays. Additionally, the schizophrenia-associated M3 domain variant GluD1-A650T produces constitutively active receptor currents, analogous to the lurcher mutation in GluD2. Pentamidine potently inhibited constitutive currents of GluD receptor variants (GluD2-T649A IC50 ~50 nM).\",\n      \"method\": \"Electrophysiological assays, biochemical complex formation assays, mutagenesis of GRID1/GRID2 cDNA\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and electrophysiology in a single rigorous study with multiple orthogonal assays\",\n      \"pmids\": [\"37944084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Homozygous missense GRID1 variants (p.Arg161His and p.Thr752Met) identified in patients with intellectual disability and spastic paraplegia impair mGlu1/5 metabotropic glutamate receptor signaling via Ca2+ and ERK pathways and impair dendrite morphology and excitatory synapse density in dissociated and organotypic slice culture neurons. Molecular modeling indicated these mutations alter the hinge between GluD1 cerebellin and D-serine binding domains. Expression, trafficking, physical interaction with mGlu1, and cerebellin binding were not conspicuously altered by these mutations.\",\n      \"method\": \"Molecular modeling, electrophysiological recordings, Ca2+ signaling assays, ERK pathway assays, neuronal culture morphological analysis in dissociated and organotypic slice cultures\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (structural modeling, electrophysiology, Ca2+ imaging, ERK biochemistry, morphological analysis) in a single study with human variant validation\",\n      \"pmids\": [\"38418578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of GluD1 (GRID1 knockout mice) leads to hyperactivity, lower anxiety, depression-like behavior, aggression, and social interaction deficits. At the molecular level, synaptoneurosome preparations from GluD1 KO mice show lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2, and PSD95 expression in the amygdala, indicating GluD1 regulates postsynaptic AMPA receptor content in a region-specific manner. D-Cycloserine rescued social interaction deficits and normalized lower GluA1 expression in prefrontal cortex.\",\n      \"method\": \"GluD1 knockout mouse behavioral analysis, synaptoneurosome biochemical fractionation, pharmacological rescue experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular phenotype (synaptoneurosome fractionation) and pharmacological rescue across multiple behavioral readouts\",\n      \"pmids\": [\"22412961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GluD1 knockout mice exhibit higher dendritic spine number, greater excitatory neurotransmission, higher synapse number, and abnormalities in LIMK1-cofilin signaling in the medial prefrontal cortex and CA1 hippocampus. A lower GluN2A/GluN2B expression ratio was also observed, indicating GluD1 is required for the developmental GluN2B-to-GluN2A NMDAR subunit switch. GluN2B-selective inhibitor Ro-25-6981 partially normalized LIMK1-cofilin signaling and reduced excess spine number.\",\n      \"method\": \"GluD1 knockout mouse spine counting, electrophysiology, western blotting, pharmacological rescue with GluN2B inhibitor\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple molecular readouts (spine morphology, electrophysiology, biochemistry) and pharmacological rescue, single lab\",\n      \"pmids\": [\"25721396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GluD1 loss in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core leads to reduced inhibitory neurotransmission, evidenced by decreased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, increased paired pulse ratio of evoked inhibitory responses (indicating reduced presynaptic release probability), and reduced GAD67 puncta (inhibitory terminals). Local ablation of GluD1 from NAc caused hypolocomotion and altered anxiety- and depression-like behaviors, while ablation from dorsal striatum produced opposite behavioral phenotypes.\",\n      \"method\": \"Conditional GluD1 knockout, whole-cell patch clamp electrophysiology, paired pulse ratio analysis, GAD67 immunofluorescence, behavioral testing\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — region-specific conditional KO with electrophysiological and morphological readouts plus behavioral phenotyping, single lab\",\n      \"pmids\": [\"34173171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional deletion of GluD1 from excitatory neurons in corticolimbic regions leads to overactive Akt-mTOR pathway, higher p62, and lower LC3-II/LC3-I ratio in the somatosensory cortex, indicating reduced autophagy. Excitatory synaptic elements were increased in number but showed an immature phenotype with lower GluA1 expression and impaired GluN2B-to-GluN2A developmental switch. Overactive Akt-mTOR signaling and impaired autophagy were also observed in dorsal striatum, prefrontal cortex, and hippocampus.\",\n      \"method\": \"Conditional GluD1 knockout mouse, western blotting for Akt-mTOR pathway components and autophagy markers (p62, LC3), synaptic puncta analysis, behavioral testing\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic KO with multiple biochemical pathway readouts (Akt-mTOR, autophagy markers, receptor subunits), single lab\",\n      \"pmids\": [\"35304260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GRID1/GluD1 directly facilitates autophagy and reduces AMPA receptor (AMPAR) expression in the central amygdala (CeA). Using a GRID1 C-terminal-derived peptide (Tat-HRSPN), GRID1 was shown to directly interact with autophagy mediators nGOPC/nPIST, BECN1, and LAMP1. During inflammatory and neuropathic pain, GRID1 and CBLN1 are downregulated in CeA alongside impaired autophagic flux and increased excitatory neurotransmission and AMPAR expression. GluD1 is preferentially expressed in PRKCD+ neurons of the CeA where BECN1 and LAMP1 co-localize.\",\n      \"method\": \"GRID1 C-terminal peptide (Tat-HRSPN) application, co-immunoprecipitation/interaction assays with BECN1/LAMP1/nGOPC, western blotting for autophagy markers, pain models (CFA inflammatory, spinal nerve ligation), electrophysiology for mEPSCs, immunofluorescence\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide-based functional intervention plus interaction assays and multiple biochemical/electrophysiological readouts, single lab\",\n      \"pmids\": [\"41147487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GRID1 expression is downregulated in iPS cells derived from both MECP2-mutated and CDKL5-mutated Rett syndrome patients and upregulated during neuronal precursor and mature neuron differentiation, consistent with a role as a postsynaptic adhesion molecule that preferentially induces inhibitory presynaptic differentiation of cortical neurons.\",\n      \"method\": \"iPS cell gene expression profiling, real-time RT-PCR in CDKL5- and MECP2-mutated cells during neuronal differentiation\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression measurement in iPS cells, no direct functional manipulation of GluD1 protein, single method\",\n      \"pmids\": [\"24916645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In rodents and non-human primates, GluD1 immunoreactivity in the lateral habenula (LHb) is primarily expressed in dendritic profiles and is strongly localized to the core of symmetric (GABAergic) synapses, with lower perisynaptic presence at asymmetric (glutamatergic) synapses. Axon terminals from the entopeduncular nucleus and lateral hypothalamus show postsynaptic GluD1 immunolabeling in LHb, as determined by anterograde tracing combined with immunogold labeling.\",\n      \"method\": \"Immunoelectron microscopy (pre- and post-embedding immunogold), anterograde tracing combined with immunogold labeling in rat and monkey tissue\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy with two orthogonal approaches (pre- and post-embedding) in two species\",\n      \"pmids\": [\"39794140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The NRXN1-CBLN1-GluD1 transsynaptic complex at VMHvl-to-arcuate AgRP/NPY neuron excitatory synapses regulates aggression. Targeted deletion of GluD1 from arcuate AgRP neurons impairs excitatory synapses from VMHvl neurons onto AgRP/NPY neurons and increases aggression. Heterozygous deficiency of Grid1 synergizes with increased UBE3A to further increase aggression, placing GluD1 as a postsynaptic component of the NRXN1-CBLN1-GluD1 transsynaptic complex required for this hypothalamic circuit.\",\n      \"method\": \"Conditional Grid1 deletion in AgRP neurons, chemogenetic/optogenetic activation, behavioral aggression assays, epistasis with Nrxn1 and Ube3a genetic manipulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic KO with circuit-level epistasis and multiple orthogonal manipulations (chemogenetics, optogenetics, genetics), preprint only\",\n      \"pmids\": [\"36909588\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Grid1 knockdown in hypothalamic neurons (via lentiviral vector) decreases Grid1 and Rfrp-3 mRNA expression but increases Gnrh mRNA. ICV injection of LV-Grid1 in prepubertal rats causes earlier vaginal opening, increased Gnrh mRNA, decreased Rfrp-3 mRNA, decreased progesterone concentration, and altered follicular development, indicating GluD1 modulates puberty onset via Gnrh and Rfrp-3 regulation in the hypothalamus.\",\n      \"method\": \"Lentiviral Grid1 knockdown in hypothalamic neurons, ICV injection in prepubertal female rats, qRT-PCR, hormone measurement (progesterone), histological ovary analysis\",\n      \"journal\": \"The Journal of veterinary medical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with mRNA/hormone readouts, no direct protein-level mechanistic validation\",\n      \"pmids\": [\"38479882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC5 inhibitor T2943 promotes H3K14 acetylation at the Grid1 promoter region, enhancing GRID1 transcription and expression. GRID1 knockdown blocks the antidepressant behavioral effect of T2943 in mice, establishing GRID1 as a downstream effector of HDAC5-dependent chromatin remodeling in the antidepressant response.\",\n      \"method\": \"CUT&Tag chromatin profiling, GRID1 knockdown, behavioral tests (forced swim, sucrose preference), HDAC5 inhibitor pharmacology\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, chromatin profiling plus KD rescue, mechanistic link between H3K14ac and GRID1 promoter inferred from CUT&Tag without direct promoter-reporter validation\",\n      \"pmids\": [\"39915556\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GluD1 (GRID1) is a postsynaptic ionotropic glutamate receptor-family protein that functions primarily as a non-classical synaptogenic scaffold rather than a conventional ligand-gated ion channel: it forms a transsynaptic bridge via cerebellin (Cbln) family proteins and presynaptic neurexins, mediates slow depolarizing currents downstream of mGlu1 receptor activation in midbrain dopamine neurons (controlling burst firing), regulates the postsynaptic content of AMPA and NMDA receptor subunits and the GluN2B-to-GluN2A developmental switch, controls dendritic spine density and excitatory/inhibitory synapse balance in cortex, hippocampus, striatum, and nucleus accumbens through both pre- and postsynaptic mechanisms, and facilitates autophagic flux via direct interactions with BECN1, LAMP1, and nGOPC/nPIST; disease-associated missense variants disrupt its cerebellin-binding domain or D-serine-binding domain, impair mGlu1/5 signaling, and certain M3-domain variants create constitutively active channels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRID1 encodes GluD1, a glutamate receptor-family protein that functions principally as a postsynaptic organizer of excitatory and inhibitory synapses across multiple brain circuits rather than as a conventional ligand-gated channel [#0, #4]. In midbrain dopamine neurons GluD1 acts downstream of the mGlu1 receptor to generate slow depolarizing currents that drive spontaneous burst firing, an activity abolished by a dominant-negative dead-pore mutant or by Grid1 knockout [#0]. At synapses GluD1 serves as the postsynaptic component of a NRXN1-CBLN1-GluD1 transsynaptic complex that specifies excitatory connectivity, as shown for VMHvl-to-AgRP/NPY hypothalamic synapses controlling aggression [#10]. Loss of GluD1 dysregulates postsynaptic receptor composition in a region-specific manner — altering AMPA receptor subunit content, impairing the developmental GluN2B-to-GluN2A NMDAR switch, and perturbing LIMK1-cofilin signaling, dendritic spine density, and synapse number in cortex, hippocampus, striatum, and nucleus accumbens [#3, #4, #5]. GluD1 additionally facilitates autophagic flux through direct interactions of its C-terminus with nGOPC/nPIST, BECN1, and LAMP1, and its loss produces overactive Akt-mTOR signaling and impaired autophagy alongside immature excitatory synapses [#6, #7]. Homozygous missense GRID1 variants cause intellectual disability with spastic paraplegia by altering the hinge between the cerebellin- and D-serine-binding domains and impairing mGlu1/5 signaling through Ca2+ and ERK pathways, while distinct variants disrupt cerebellin binding or create constitutively active channels [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that GluD1 controls postsynaptic AMPA receptor content and behavior in a region-specific way, defining it as a synaptic regulator rather than a passive structural subunit.\",\n      \"evidence\": \"Grid1 knockout mouse behavior, synaptoneurosome fractionation, and D-cycloserine pharmacological rescue\",\n      \"pmids\": [\"22412961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether AMPAR changes are direct or secondary to circuit remodeling\", \"No molecular mechanism linking GluD1 to receptor subunit trafficking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed GluD1 is required for the developmental GluN2B-to-GluN2A NMDAR switch and constrains dendritic spine number via LIMK1-cofilin signaling, connecting GluD1 to spine maturation.\",\n      \"evidence\": \"Grid1 knockout spine counting, electrophysiology, western blotting, and GluN2B-inhibitor rescue in mPFC and CA1\",\n      \"pmids\": [\"25721396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling GluD1 to LIMK1-cofilin not defined\", \"Direct versus indirect control of NMDAR subunit composition unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Answered how GluD1 contributes to signaling without classical gating: it acts downstream of mGlu1 to produce slow depolarizing currents driving dopamine neuron burst firing.\",\n      \"evidence\": \"HEK co-expression electrophysiology, dominant-negative dead-pore mutant in midbrain slices, and in vivo recordings in Grid1 knockout mice\",\n      \"pmids\": [\"28696429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mGlu1-GluD1 coupling not determined\", \"Whether ion flux through GluD1 itself or a downstream conductance carries the current\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended GluD1 function to inhibitory transmission, showing region-specific loss reduces inhibitory synapse number and presynaptic release with opposing behavioral effects in NAc versus dorsal striatum.\",\n      \"evidence\": \"Conditional Grid1 knockout, patch clamp with paired-pulse analysis, GAD67 immunofluorescence, and behavioral testing\",\n      \"pmids\": [\"34173171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a postsynaptic protein lowers presynaptic release probability unclear\", \"Transsynaptic partner mediating inhibitory effect not identified in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked GluD1 loss to overactive Akt-mTOR signaling and impaired autophagy accompanying immature excitatory synapses, introducing an autophagy axis to GluD1 biology.\",\n      \"evidence\": \"Conditional Grid1 knockout, western blotting for Akt-mTOR and autophagy markers (p62, LC3), and synaptic puncta analysis\",\n      \"pmids\": [\"35304260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct molecular link between GluD1 and autophagy machinery\", \"Causal direction between synapse immaturity and autophagy defect unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined GluD1 as the postsynaptic component of a NRXN1-CBLN1-GluD1 transsynaptic complex specifying a hypothalamic excitatory circuit that regulates aggression.\",\n      \"evidence\": \"Conditional Grid1 deletion in AgRP neurons, chemogenetic/optogenetic manipulation, aggression assays, and epistasis with Nrxn1 and Ube3a (preprint)\",\n      \"pmids\": [\"36909588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Biochemical reconstitution of the tripartite complex not shown in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected GRID1 to human Mendelian disease, showing homozygous missense variants cause intellectual disability and spastic paraplegia by altering the cerebellin/D-serine domain hinge and impairing mGlu1/5 Ca2+ and ERK signaling.\",\n      \"evidence\": \"Patient variant identification, molecular modeling, electrophysiology, Ca2+ and ERK assays, and neuronal morphology in dissociated and slice cultures\",\n      \"pmids\": [\"38418578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variants did not conspicuously alter expression, trafficking, mGlu1 interaction, or cerebellin binding, leaving precise signaling lesion undefined\", \"No in vivo model of the human variants\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how distinct variant classes act, distinguishing cerebellin-binding-disrupting amino-terminal variants from M3-domain variants that produce constitutively active currents, with pentamidine identified as an inhibitor.\",\n      \"evidence\": \"Mutagenesis of GRID1/GRID2 cDNA, electrophysiology, and biochemical complex-formation assays\",\n      \"pmids\": [\"37944084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of constitutively active variants not tested\", \"Therapeutic relevance of pentamidine inhibition not validated in disease models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided direct evidence that GluD1 physically engages autophagy machinery, with its C-terminus interacting with nGOPC/nPIST, BECN1, and LAMP1 to promote autophagy and limit AMPAR expression in central amygdala pain circuits.\",\n      \"evidence\": \"Tat-HRSPN C-terminal peptide intervention, interaction assays with BECN1/LAMP1/nGOPC, autophagy marker blotting, pain models, and mEPSC recordings\",\n      \"pmids\": [\"41147487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction assays from a single lab without reciprocal structural validation\", \"Stoichiometry and regulation of the GluD1-autophagy interactions unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the precise synaptic localization of GluD1, placing it at the core of symmetric (GABAergic) synapses in the lateral habenula, consistent with a role in organizing inhibitory contacts.\",\n      \"evidence\": \"Pre- and post-embedding immunogold electron microscopy with anterograde tracing in rat and monkey lateral habenula\",\n      \"pmids\": [\"39794140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GABAergic-synapse localization not tested here\", \"Transsynaptic partners at these symmetric synapses not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GluD1's transsynaptic adhesion role, its mGlu1-coupled conductance, and its direct autophagy interactions are integrated into a single molecular mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model unifying ligand-binding, channel, and C-terminal autophagy functions\", \"Whether autophagy regulation and synaptic organization are coupled or independent activities\", \"Causal mechanism by which a postsynaptic protein controls presynaptic release and inhibitory connectivity\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [10, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"NRXN1-CBLN1-GluD1 transsynaptic complex\"],\n    \"partners\": [\"CBLN1\", \"CBLN2\", \"NRXN1\", \"GRM1\", \"BECN1\", \"LAMP1\", \"GOPC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}