{"gene":"CPLX1","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2009,"finding":"Complexin I (CPLX1) is required at the endbulb of Held auditory synapse: in CPX I knockout mice, resting release probability at endbulb of Held synapses was reduced, synaptic transmission outlasted the stimulus (impaired synchronization), and sound onset/offset processing in the cochlear nucleus was abnormal, despite normal Ca2+-dependent exocytosis in inner hair cells and normal sound encoding in the cochlea.","method":"Cplx1 knockout mice, auditory brainstem responses, in vitro electrophysiology (patch-clamp), in vivo single-unit recordings, computational modeling","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and electrophysiological phenotype, multiple orthogonal methods, replicated in vivo and in vitro","pmids":["19553439"],"is_preprint":false},{"year":2005,"finding":"CPLX1 is essential for normal motor function, exploratory behavior, and emotional reactivity in mice: Cplx1 knockout mice develop severe ataxia (in absence of cerebellar degeneration), profound deficits in motor coordination, dystonia, resting tremor, impaired grooming/rearing, reduced exploration, and deficits in emotional reactivity.","method":"Cplx1 knockout mice, behavioral battery (rotarod, gait analysis, open field, swim test, neuromuscular strength tests)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple well-defined behavioral/motor phenotypes across multiple paradigms","pmids":["16000319"],"is_preprint":false},{"year":2007,"finding":"CPLX1 is required for normal social behavior: Cplx1 knockout mice fail to show preference for social novelty and lack normal aggressive behavior in resident-intruder paradigm, despite normal olfactory discrimination, indicating a specific role for CPLX1 in social interaction circuitry.","method":"Cplx1 knockout mice, social transmission of food preference, resident-intruder paradigm, social novelty preference, two-choice swim tank cognitive testing","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific behavioral phenotypes and appropriate controls ruling out cognitive or olfactory confounds","pmids":["17652102"],"is_preprint":false},{"year":2006,"finding":"CPLX1 is required for normal early postnatal motor development: Cplx1 knockout mice develop ataxia by postnatal day 7 and show marked deficits in postural skills and complex movement by P21.","method":"Cplx1 knockout mice, longitudinal developmental behavioral assessment (postural skills, complex movement tasks)","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — clean KO with temporally defined developmental phenotype","pmids":["17188502"],"is_preprint":false},{"year":2015,"finding":"CPLX1 serves dual facilitating and clamping functions at the calyx of Held synapse: genetic ablation of Cplx1 causes reduced spontaneous and evoked transmission (decreased release probability, partly due to less tight Ca2+ channel–docked SV coupling) and excessive asynchronous release after stimulation, without altering action potential waveforms, Ca2+ influx, readily releasable pool size, or quantal size.","method":"Cplx1 knockout mice, calyx of Held patch-clamp electrophysiology (evoked and spontaneous EPSCs, Ca2+ channel–SV coupling analysis), electron microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — native synapse preparation, multiple electrophysiological parameters, EM, rigorous controls","pmids":["26019341"],"is_preprint":false},{"year":2004,"finding":"CPLX1 controls Ca2+-stimulated exocytosis in pancreatic beta-cells: overexpression or siRNA-mediated knockdown of CPLX1 strongly impairs glucose-, leucine-, and KCl-stimulated insulin secretion, particularly in the early secretory phase. CPLX1 expression in beta-cells is controlled by a neuron restrictive silencer element (NRSE) bound by the transcriptional repressor REST.","method":"siRNA knockdown and overexpression in insulin-secreting cell lines and primary islets, secretion assays (glucose, leucine, KCl stimulation), REST binding to NRSE by EMSA/reporter assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation (KD and OE) with defined secretory phenotype and transcriptional mechanism","pmids":["15126625"],"is_preprint":false},{"year":2015,"finding":"miR-137 directly targets CPLX1 (along with Nsf and Syt1) in presynaptic neurons: miR-137 gain of function downregulates CPLX1 protein, leading to impaired vesicle release, changes in synaptic vesicle pool distribution, impaired mossy fiber LTP, and hippocampus-dependent memory deficits.","method":"Human iPSC-derived neurons with minor alleles of MIR137 SNPs, miR-137 overexpression/sequestration in vivo and in vitro, synaptic vesicle pool analysis (EM), LTP recordings, behavioral tests","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function and rescue experiments in both human neurons and in vivo mouse models, multiple orthogonal methods","pmids":["26005852"],"is_preprint":false},{"year":2014,"finding":"PGC-1α is required for transcriptional regulation of CPLX1 in parvalbumin-positive interneurons: conditional deletion of PGC-1α in PV+ neurons decreases Cplx1 transcript, promotes asynchronous GABA release, and impairs long-term memory.","method":"PV-specific conditional PGC-1α knockout mice, qRT-PCR, electrophysiology (asynchronous GABA release), behavioral memory tests, microarray in PGC-1α overexpressing neuroblastoma cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific conditional KO with transcriptional, electrophysiological, and behavioral phenotypes","pmids":["25339750"],"is_preprint":false},{"year":2014,"finding":"CPLX1 is enriched in SNARE complexes in schizophrenia orbitofrontal cortex: immunoprecipitation of SNAP25 showed ~2-fold enrichment of CPLX1 (along with syntaxin and Munc18-1) in schizophrenia OFC; blue-native PAGE identified an upregulated 200-kDa SNARE-CPLX1 species and downregulated 550-kDa CPLX1-containing oligomers in schizophrenia.","method":"Co-immunoprecipitation (SNAP25 pulldown), blue-native PAGE, two-cohort postmortem human brain samples","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and native PAGE in two independent human cohorts, but postmortem tissue without functional manipulation","pmids":["25662103"],"is_preprint":false},{"year":2018,"finding":"Frontal CPLX1/CPLX2 ratio in 500-kDa heteromeric species (representing inhibitory/excitatory input balance) is associated with cognitive function and rate of cognitive decline in aging, independent of neuropathology and synapse density; reconstitution assays with recombinant SNARE proteins confirmed complex formation.","method":"Blue-native gel electrophoresis of postmortem human frontal and temporal cortex, reconstitution assays with recombinant proteins, multivariate analyses in longitudinal aging cohort (MAP)","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — native PAGE with reconstitution, but associative human postmortem data without direct functional manipulation","pmids":["29496544"],"is_preprint":false},{"year":2015,"finding":"CPLX1 expression is regulated by PGC-1α in cerebellar Purkinje cells: PGC-1α knockout mice show reduced Cplx1 transcript in cerebellum, Purkinje cell loss by 6 weeks, and a 50% reduction in Purkinje cell spike rate; 50% of cerebellar PGC-1α expression is attributable to PV+ neurons.","method":"PGC-1α knockout mice, PV-specific conditional knockout, qRT-PCR, stereological cell counts, in vivo electrophysiology (Purkinje cell spike rate)","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 — global and conditional KO with defined electrophysiological and histological phenotypes","pmids":["25610371"],"is_preprint":false},{"year":2019,"finding":"CPLX1 knockout rats exhibit ataxia, dystonia, exploratory and movement deficits, increased anxiety, sensory deficits, decreased dendritic branching in spinal motor neurons, and abnormal stomach/intestine histomorphology leading to early death, establishing CPLX1 as required for normal motor neuron morphology and gastrointestinal function.","method":"CRISPR/Cas9 Cplx1 knockout rats, behavioral battery, Nissl staining, HE staining, Golgi staining of spinal motor neurons","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 2 — clean KO in second species with direct histological evidence of dendritic and visceral phenotypes","pmids":["31875236"],"is_preprint":false},{"year":2018,"finding":"Loss of CPX1/CPLX1 in the nigrostriatal pathway is confirmed in Cplx1-null mice: nigrostriatal pathway is compromised in Cplx1-null mice, supporting CPLX1's functional role in dopaminergic neurotransmission.","method":"Cplx1-null mice, verification of nigrostriatal pathway deficit (used as proof of principle in PD candidate gene study)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo validation in KO mice but limited mechanistic detail reported in abstract","pmids":["29499164"],"is_preprint":false},{"year":2024,"finding":"CPLX1 expressed in parvalbumin-positive neurons facilitates neurotransmitter release to enhance ultrasound neurotransmission: microbat PV+ neurons highly express CPLX1; perturbation of Cplx1 specifically in PV+ neurons impairs ultrasound perception in mouse auditory cortex; CPLX1 functions throughout the auditory pathway in echolocating microbats.","method":"Single-nucleus RNA-seq atlas (microbat vs megabat), AAV-mediated Cplx1 perturbation in mouse PV+ neurons, ultrasound perception behavioral assays, silencing of PV+ neurons","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific in vivo perturbation with defined behavioral phenotype, cross-species comparison with functional validation","pmids":["38834904"],"is_preprint":false},{"year":2025,"finding":"LINC02449-G allele overexpression upregulates CPLX1 in the mPFC, enhancing excitatory synaptic transmission in the mPFC-NAc circuit and causing social deficits and repetitive behaviors; riluzole normalizes elevated Cplx1 expression and rescues both behavioral and electrophysiological abnormalities.","method":"AAV-mediated mPFC LINC02449-G overexpression in mice, whole-cell patch-clamp (mEPSC in NAc neurons), behavioral assays (social interaction, grooming, marble-burying), riluzole pharmacological rescue","journal":"Nature communications / Schizophrenia bulletin","confidence":"High","confidence_rationale":"Tier 2 — directional circuit manipulation with electrophysiology, behavior, and pharmacological rescue across two studies","pmids":["41188235","41863379"],"is_preprint":false},{"year":2021,"finding":"PGC-1α-specific knockout in PV+ neurons blocks activity-dependent regulation of CPLX1 (and SYT2), reduces the intensity of preictal discharges, and slows ictogenesis, indicating CPLX1 in PV+ interneurons contributes to seizure generation dynamics.","method":"PV-specific PGC-1α conditional knockout mice, 0 Mg2+ ictogenic brain slice model, multi-electrode array recordings, PV interneuron and pyramidal cell firing rate analysis","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with electrophysiological phenotype, but CPLX1 role is inferred downstream of PGC-1α manipulation","pmids":["34788174"],"is_preprint":false},{"year":2015,"finding":"The conserved SNARE-binding domain of complexin (Cplx3, a ribbon-synapse-specific paralogue) interferes with the SNARE complex to prevent spontaneous fusion and facilitate evoked release at ribbon synapses; an inhibitory peptide of this domain increased spontaneous SV fusion, depleted reserve SVs, and reduced Ca2+-evoked fusion — establishing a dual clamp/facilitator mechanism for complexins at these synapses.","method":"Whole-cell patch-clamp capacitance measurements and FM-dye destaining in mouse retinal bipolar neuron terminals, inhibitory peptide introduction via patch pipette, electron microscopy","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro peptide interference at native synapse with direct fusion readout, but uses Cplx3 not Cplx1; establishes shared mechanism for the complexin family","pmids":["25740533"],"is_preprint":false}],"current_model":"CPLX1 (Complexin I) is a presynaptic protein that binds the SNARE complex and serves dual functions: it stabilizes newly primed synaptic vesicles (clamping function, preventing premature fusion) and facilitates rapid Ca2+-triggered exocytosis; loss of CPLX1 reduces release probability and tight Ca2+-channel–vesicle coupling while causing excessive asynchronous release, resulting in profound ataxia, social and motor deficits in vivo, and its transcription is regulated by PGC-1α via NRF-1 specifically in parvalbumin-positive interneurons, where it supports synchronous GABAergic neurotransmission."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that CPLX1 functions outside neurons — in pancreatic β-cells it controls Ca²⁺-stimulated insulin secretion, and its expression is transcriptionally repressed by REST via an NRSE, revealing tissue-specific regulation of this presynaptic protein.","evidence":"siRNA knockdown and overexpression in β-cell lines/primary islets with secretion assays; EMSA and reporter assays for REST–NRSE binding","pmids":["15126625"],"confidence":"High","gaps":["Mechanism by which both overexpression and knockdown impair secretion is unclear","Whether CPLX1 interacts with the same SNARE partners in β-cells as in neurons not established"]},{"year":2005,"claim":"Demonstrating that CPLX1 loss causes severe neurological phenotypes — Cplx1 KO mice develop early ataxia, dystonia, tremor, and motor coordination deficits without cerebellar degeneration, establishing CPLX1 as essential for motor circuit function in vivo.","evidence":"Cplx1 knockout mice assessed with comprehensive behavioral battery (rotarod, gait analysis, open field, swim test)","pmids":["16000319"],"confidence":"High","gaps":["Synaptic mechanism underlying motor phenotypes not yet identified","Whether motor deficits reflect cerebellar, spinal, or distributed circuit dysfunction not resolved"]},{"year":2006,"claim":"Defining the developmental onset of CPLX1 dependence — ataxia appears by postnatal day 7, indicating CPLX1 is required during the critical period of motor circuit maturation.","evidence":"Longitudinal developmental behavioral assessment in Cplx1 KO mice from P7 to P21","pmids":["17188502"],"confidence":"High","gaps":["Whether early ataxia reflects a developmental versus maintenance role is unresolved","Cell types responsible for the early phenotype not identified"]},{"year":2007,"claim":"Extending CPLX1's behavioral role beyond motor function — KO mice lack social novelty preference and normal aggression with intact olfaction, implicating CPLX1 in social circuit neurotransmission specifically.","evidence":"Cplx1 KO mice tested in social novelty preference, resident-intruder aggression, and olfactory discrimination assays","pmids":["17652102"],"confidence":"High","gaps":["Neural circuits and transmitter systems mediating the social deficits not mapped","Whether social deficits are secondary to motor impairment not fully excluded"]},{"year":2009,"claim":"Revealing CPLX1's synapse-level mechanism in an identified central synapse — at the endbulb of Held, CPLX1 loss reduces release probability and desynchronizes transmission while cochlear encoding remains normal, localizing the defect to central synaptic release.","evidence":"Patch-clamp electrophysiology, in vivo single-unit recordings, and auditory brainstem responses in Cplx1 KO mice","pmids":["19553439"],"confidence":"High","gaps":["Whether reduced release probability reflects a priming, docking, or Ca²⁺-coupling defect not distinguished","Compensatory changes by other complexin paralogues not assessed"]},{"year":2014,"claim":"Identifying a transcriptional pathway controlling CPLX1 in inhibitory interneurons — PGC-1α in PV+ neurons is required for CPLX1 expression, and its conditional loss phenocopies CPLX1 deficiency with asynchronous GABA release and memory impairment, linking mitochondrial transcriptional coactivation to presynaptic vesicle release control.","evidence":"PV-specific conditional PGC-1α knockout mice with qRT-PCR, electrophysiology (asynchronous GABA release), and behavioral memory tests","pmids":["25339750"],"confidence":"High","gaps":["Whether PGC-1α acts on the CPLX1 promoter directly or via NRF-1 was established elsewhere but ChIP at native locus not shown","Contribution of other PGC-1α targets (e.g., SYT2) to the phenotype not dissected"]},{"year":2015,"claim":"Resolving the dual clamp/facilitator mechanism at a mammalian central synapse — at the calyx of Held, CPLX1 deletion reduces evoked release probability partly through loosened Ca²⁺-channel–vesicle coupling and causes excessive asynchronous release, without altering vesicle pool size, quantal size, or Ca²⁺ influx, establishing CPLX1 as a fusion clamp and synchronous release facilitator simultaneously.","evidence":"Calyx of Held patch-clamp electrophysiology and electron microscopy in Cplx1 KO mice","pmids":["26019341"],"confidence":"High","gaps":["Structural basis for how CPLX1 tightens Ca²⁺ channel–vesicle coupling not determined","Whether the dual function involves distinct CPLX1 domains at this synapse not tested"]},{"year":2015,"claim":"Extending PGC-1α–CPLX1 regulation to cerebellar Purkinje cells — PGC-1α KO reduces CPLX1 in cerebellum and causes Purkinje cell loss and reduced spike rate, providing a mechanistic link to the ataxia phenotype of CPLX1 loss.","evidence":"PGC-1α global and PV-conditional KO mice, qRT-PCR, stereological Purkinje cell counts, in vivo electrophysiology","pmids":["25610371"],"confidence":"High","gaps":["Whether Purkinje cell loss is due to CPLX1 reduction specifically or other PGC-1α targets remains untested","Whether CPLX1 restoration rescues the Purkinje cell phenotype not attempted"]},{"year":2015,"claim":"miR-137, a schizophrenia-associated microRNA, directly targets CPLX1 mRNA and its downregulation impairs vesicle release, mossy fiber LTP, and hippocampal memory, establishing a post-transcriptional regulatory layer for CPLX1 with psychiatric relevance.","evidence":"miR-137 gain/loss of function in human iPSC neurons and in vivo mouse hippocampus, EM vesicle pool analysis, LTP recordings, behavioral tests","pmids":["26005852"],"confidence":"High","gaps":["Relative contribution of CPLX1 versus NSF and SYT1 (co-targets) to miR-137 phenotype not separated","Whether endogenous miR-137 variation significantly modulates CPLX1 levels in human brain unknown"]},{"year":2018,"claim":"CPLX1 participates in high-molecular-weight SNARE-containing heteromeric complexes in human cortex, and the CPLX1/CPLX2 ratio in these complexes correlates with cognitive function during aging independently of neuropathology, suggesting stoichiometric balance of complexin paralogues matters for circuit performance.","evidence":"Blue-native PAGE and reconstitution assays with recombinant SNARE proteins in postmortem human cortex from a longitudinal aging cohort","pmids":["29496544"],"confidence":"Medium","gaps":["Causal relationship between CPLX1/CPLX2 ratio and cognitive decline not established","Functional significance of the 500-kDa species not tested in living systems"]},{"year":2019,"claim":"Cross-species validation in rat confirmed CPLX1 necessity for motor function and revealed additional phenotypes — decreased dendritic branching in spinal motor neurons and abnormal gastrointestinal histomorphology, expanding CPLX1's role beyond synaptic transmission to neuronal morphology and visceral innervation.","evidence":"CRISPR/Cas9 Cplx1 KO rats with behavioral battery, Golgi staining of spinal motor neurons, GI histology","pmids":["31875236"],"confidence":"High","gaps":["Whether dendritic branching defects are cell-autonomous or secondary to activity changes unknown","Mechanism of GI dysfunction (enteric neuron vs. smooth muscle) not determined"]},{"year":2021,"claim":"CPLX1 in PV+ interneurons contributes to seizure dynamics — PV-specific PGC-1α deletion, which reduces CPLX1, slows ictogenesis and reduces preictal discharge intensity, indicating that synchronous PV+ neuron output controlled by CPLX1 can paradoxically promote seizure initiation.","evidence":"PV-specific PGC-1α conditional KO, 0-Mg²⁺ ictogenic brain slice model, multi-electrode array recordings","pmids":["34788174"],"confidence":"Medium","gaps":["CPLX1's role is inferred through PGC-1α manipulation rather than direct CPLX1 perturbation","Whether CPLX1 restoration in PV+ neurons is sufficient to re-accelerate ictogenesis untested"]},{"year":2024,"claim":"Evolutionary specialization of CPLX1 expression in PV+ neurons supports ultrasound neurotransmission — echolocating microbats selectively upregulate CPLX1 in PV+ auditory neurons, and cell-type-specific perturbation of Cplx1 in mouse PV+ neurons impairs ultrasound perception, directly linking CPLX1 to temporal precision of sensory processing.","evidence":"Cross-species single-nucleus RNA-seq, AAV-mediated Cplx1 perturbation in mouse PV+ neurons, ultrasound perception behavioral assays","pmids":["38834904"],"confidence":"High","gaps":["Specific synaptic parameters altered by Cplx1 perturbation in auditory PV+ neurons not measured","Whether CPLX1 upregulation is necessary and sufficient for echolocation ability untested"]},{"year":2025,"claim":"Circuit-level overexpression of CPLX1 can be pathogenic — LINC02449-G-driven upregulation of CPLX1 in mPFC enhances excitatory transmission in mPFC-NAc projections and causes social deficits and repetitive behaviors, which are rescued by riluzole normalization of Cplx1, demonstrating that bidirectional CPLX1 dysregulation disrupts circuit function.","evidence":"AAV-mediated mPFC overexpression in mice, whole-cell patch-clamp (mEPSC in NAc), behavioral assays, riluzole pharmacological rescue","pmids":["41188235","41863379"],"confidence":"High","gaps":["Whether riluzole acts specifically through CPLX1 or has additional targets in this circuit not resolved","LINC02449 mechanism of CPLX1 upregulation not fully characterized"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for CPLX1's dual clamp/facilitator function at native SNARE complexes; whether CPLX1's role in Ca²⁺-channel–vesicle coupling involves direct physical interaction with Ca²⁺ channels; and whether CPLX1 dysregulation is a causal driver (rather than correlate) of cognitive decline in aging and psychiatric disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of CPLX1 bound to the full SNARE complex at a mammalian synapse","Causal relationship between CPLX1 stoichiometry in SNARE complexes and human cognitive phenotypes not demonstrated","Cell-autonomous versus circuit-level contributions to motor and social phenotypes not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,16]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,7,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,5,16]}],"complexes":["SNARE complex"],"partners":["SNAP25","STX1A","SYT1","NSF","STXBP1","PPARGC1A"],"other_free_text":[]},"mechanistic_narrative":"CPLX1 (Complexin I) is a presynaptic SNARE-complex-binding protein that exerts dual control over neurotransmitter release: it clamps spontaneous vesicle fusion to prevent premature exocytosis and simultaneously facilitates rapid Ca²⁺-triggered synchronous release, with its loss reducing release probability, loosening Ca²⁺-channel–vesicle coupling, and promoting excessive asynchronous release [PMID:26019341, PMID:25740533]. CPLX1 is prominently expressed in parvalbumin-positive (PV+) interneurons, where its transcription is driven by PGC-1α via NRF-1, and its depletion impairs synchronous GABAergic transmission, contributes to seizure dynamics, and disrupts long-term memory [PMID:25339750, PMID:25610371, PMID:34788174]. Genetic ablation of CPLX1 in mice and rats produces severe early-onset ataxia, dystonia, social behavior deficits, reduced dendritic branching in motor neurons, gastrointestinal dysfunction, and compromised nigrostriatal dopaminergic signaling, while circuit-level overexpression in the medial prefrontal cortex enhances excitatory transmission and causes social deficits and repetitive behaviors rescuable by riluzole [PMID:16000319, PMID:31875236, PMID:41188235]. Beyond neurons, CPLX1 regulates Ca²⁺-stimulated insulin secretion in pancreatic β-cells, where its expression is controlled by REST via a neuron-restrictive silencer element [PMID:15126625]."},"prefetch_data":{"uniprot":{"accession":"O14810","full_name":"Complexin-1","aliases":["Complexin I","CPX I","Synaphin-2"],"length_aa":134,"mass_kda":15.0,"function":"Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles (PubMed:21785414). Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse (PubMed:21785414). Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior","subcellular_location":"Cytoplasm, cytosol; Perikaryon; Presynapse","url":"https://www.uniprot.org/uniprotkb/O14810/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPLX1","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/CPLX1","total_profiled":1310},"omim":[{"mim_id":"617976","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 63; DEE63","url":"https://www.omim.org/entry/617976"},{"mim_id":"605033","title":"COMPLEXIN 2; CPLX2","url":"https://www.omim.org/entry/605033"},{"mim_id":"605032","title":"COMPLEXIN 1; CPLX1","url":"https://www.omim.org/entry/605032"},{"mim_id":"308350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 1; DEE1","url":"https://www.omim.org/entry/308350"},{"mim_id":"185605","title":"SYNAPTOTAGMIN 1; SYT1","url":"https://www.omim.org/entry/185605"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":231.0}],"url":"https://www.proteinatlas.org/search/CPLX1"},"hgnc":{"alias_symbol":["CPX-I"],"prev_symbol":[]},"alphafold":{"accession":"O14810","domains":[{"cath_id":"1.20.5","chopping":"37-91","consensus_level":"medium","plddt":82.7016,"start":37,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14810","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14810-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14810-F1-predicted_aligned_error_v6.png","plddt_mean":71.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPLX1","jax_strain_url":"https://www.jax.org/strain/search?query=CPLX1"},"sequence":{"accession":"O14810","fasta_url":"https://rest.uniprot.org/uniprotkb/O14810.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14810/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14810"}},"corpus_meta":[{"pmid":"26539891","id":"PMC_26539891","title":"Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26539891","citation_count":253,"is_preprint":false},{"pmid":"26005852","id":"PMC_26005852","title":"The schizophrenia risk gene product miR-137 alters presynaptic plasticity.","date":"2015","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26005852","citation_count":176,"is_preprint":false},{"pmid":"26540184","id":"PMC_26540184","title":"Cattle Sex-Specific Recombination and Genetic Control from a Large Pedigree Analysis.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26540184","citation_count":142,"is_preprint":false},{"pmid":"27029733","id":"PMC_27029733","title":"Conserved Genetic Architecture Underlying Individual Recombination Rate Variation in a Wild Population of Soay Sheep (Ovis aries).","date":"2016","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27029733","citation_count":124,"is_preprint":false},{"pmid":"32609320","id":"PMC_32609320","title":"Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.","date":"2020","source":"JAMA psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32609320","citation_count":108,"is_preprint":false},{"pmid":"29499164","id":"PMC_29499164","title":"Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29499164","citation_count":96,"is_preprint":false},{"pmid":"19553439","id":"PMC_19553439","title":"Complexin-I is required for high-fidelity transmission at the endbulb of Held auditory synapse.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19553439","citation_count":90,"is_preprint":false},{"pmid":"16000319","id":"PMC_16000319","title":"Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16000319","citation_count":63,"is_preprint":false},{"pmid":"26019341","id":"PMC_26019341","title":"Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion at the mouse calyx of held synapse.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26019341","citation_count":60,"is_preprint":false},{"pmid":"15126625","id":"PMC_15126625","title":"Complexin I regulates glucose-induced secretion in pancreatic beta-cells.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15126625","citation_count":58,"is_preprint":false},{"pmid":"29635364","id":"PMC_29635364","title":"MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29635364","citation_count":57,"is_preprint":false},{"pmid":"25339750","id":"PMC_25339750","title":"PGC-1α provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25339750","citation_count":57,"is_preprint":false},{"pmid":"26750116","id":"PMC_26750116","title":"Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding.","date":"2016","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/26750116","citation_count":56,"is_preprint":false},{"pmid":"25662103","id":"PMC_25662103","title":"Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia.","date":"2014","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25662103","citation_count":52,"is_preprint":false},{"pmid":"28608594","id":"PMC_28608594","title":"Melatonin ameliorates anxiety and depression-like behaviors and modulates proteomic changes in triple transgenic mice of Alzheimer's disease.","date":"2017","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28608594","citation_count":51,"is_preprint":false},{"pmid":"17652102","id":"PMC_17652102","title":"Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17652102","citation_count":44,"is_preprint":false},{"pmid":"20888897","id":"PMC_20888897","title":"Molecular evidence that cortical synaptic growth predominates during the first decade of life in humans.","date":"2010","source":"International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20888897","citation_count":42,"is_preprint":false},{"pmid":"25610371","id":"PMC_25610371","title":"Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α.","date":"2015","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25610371","citation_count":39,"is_preprint":false},{"pmid":"29496544","id":"PMC_29496544","title":"Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age.","date":"2018","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29496544","citation_count":35,"is_preprint":false},{"pmid":"26683626","id":"PMC_26683626","title":"Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia.","date":"2015","source":"Schizophrenia bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/26683626","citation_count":35,"is_preprint":false},{"pmid":"28422131","id":"PMC_28422131","title":"Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28422131","citation_count":33,"is_preprint":false},{"pmid":"17188502","id":"PMC_17188502","title":"Early motor development is abnormal in complexin 1 knockout mice.","date":"2006","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/17188502","citation_count":32,"is_preprint":false},{"pmid":"25740533","id":"PMC_25740533","title":"Functional roles of complexin in neurotransmitter release at ribbon synapses of mouse retinal bipolar neurons.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25740533","citation_count":30,"is_preprint":false},{"pmid":"35721735","id":"PMC_35721735","title":"Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35721735","citation_count":29,"is_preprint":false},{"pmid":"24738919","id":"PMC_24738919","title":"Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder.","date":"2014","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/24738919","citation_count":27,"is_preprint":false},{"pmid":"24357569","id":"PMC_24357569","title":"Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24357569","citation_count":26,"is_preprint":false},{"pmid":"34305524","id":"PMC_34305524","title":"Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod.","date":"2021","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34305524","citation_count":25,"is_preprint":false},{"pmid":"25112678","id":"PMC_25112678","title":"Complexin-1 and Foxp1 Expression Changes Are Novel Brain Effects of Alpha-Synuclein Pathology.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25112678","citation_count":23,"is_preprint":false},{"pmid":"27496128","id":"PMC_27496128","title":"Genome-wide association study revealed genomic regions related to white/red earlobe color trait in the Rhode Island Red chickens.","date":"2016","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27496128","citation_count":23,"is_preprint":false},{"pmid":"32824035","id":"PMC_32824035","title":"Genome-Wide Assessment of Runs of Homozygosity in Chinese Wagyu Beef Cattle.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32824035","citation_count":22,"is_preprint":false},{"pmid":"19346281","id":"PMC_19346281","title":"Proteomic analysis of rat hippocampus exposed to the antidepressant paroxetine.","date":"2009","source":"Journal of psychopharmacology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19346281","citation_count":21,"is_preprint":false},{"pmid":"28108469","id":"PMC_28108469","title":"Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.","date":"2017","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/28108469","citation_count":20,"is_preprint":false},{"pmid":"18714005","id":"PMC_18714005","title":"A polypyrimidine tract-binding protein-dependent pathway of mRNA stability initiates with CpG activation of primary B cells.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18714005","citation_count":19,"is_preprint":false},{"pmid":"30430034","id":"PMC_30430034","title":"Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.","date":"2018","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30430034","citation_count":19,"is_preprint":false},{"pmid":"36344488","id":"PMC_36344488","title":"Epigenome-wide DNA methylation analysis of whole blood cells derived from patients with GAD and OCD in the Chinese Han population.","date":"2022","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36344488","citation_count":18,"is_preprint":false},{"pmid":"31136779","id":"PMC_31136779","title":"Long-term iron exposure causes widespread molecular alterations associated with memory impairment in mice.","date":"2019","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/31136779","citation_count":18,"is_preprint":false},{"pmid":"36797040","id":"PMC_36797040","title":"Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing.","date":"2023","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/36797040","citation_count":16,"is_preprint":false},{"pmid":"21426264","id":"PMC_21426264","title":"Candidate pathway association study in cocaine dependence: the control of neurotransmitter release.","date":"2011","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/21426264","citation_count":13,"is_preprint":false},{"pmid":"38671141","id":"PMC_38671141","title":"GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38671141","citation_count":12,"is_preprint":false},{"pmid":"32900904","id":"PMC_32900904","title":"Transcriptome Analysis of the Chicken Follicular Theca Cells with miR-135a-5p Suppressed.","date":"2020","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/32900904","citation_count":12,"is_preprint":false},{"pmid":"35359639","id":"PMC_35359639","title":"Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes.","date":"2022","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35359639","citation_count":11,"is_preprint":false},{"pmid":"31875236","id":"PMC_31875236","title":"Complexin I knockout rats exhibit a complex neurobehavioral phenotype including profound ataxia and marked deficits in lifespan.","date":"2019","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31875236","citation_count":10,"is_preprint":false},{"pmid":"25698939","id":"PMC_25698939","title":"Red nucleus and rubrospinal tract disorganization in the absence of Pou4f1.","date":"2015","source":"Frontiers in neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/25698939","citation_count":10,"is_preprint":false},{"pmid":"21110949","id":"PMC_21110949","title":"Identification of complexin II in astrocytes: a possible regulator of glutamate release in these cells.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21110949","citation_count":10,"is_preprint":false},{"pmid":"35726075","id":"PMC_35726075","title":"Transcriptomic profiling on localized gastric cancer identified CPLX1 as a gene promoting malignant phenotype of gastric cancer and a predictor of recurrence after surgery and subsequent chemotherapy.","date":"2022","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/35726075","citation_count":8,"is_preprint":false},{"pmid":"36675068","id":"PMC_36675068","title":"Involvement of miR-135a-5p Downregulation in Acute and Chronic Stress Response in the Prefrontal Cortex of Rats.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36675068","citation_count":8,"is_preprint":false},{"pmid":"29118371","id":"PMC_29118371","title":"Genetic association analysis of microRNA137 and its target complex 1 with schizophrenia in Han Chinese.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29118371","citation_count":7,"is_preprint":false},{"pmid":"36545122","id":"PMC_36545122","title":"Proteomic analysis of spinal cord tissue in a rat model of cancer-induced bone pain.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36545122","citation_count":6,"is_preprint":false},{"pmid":"38834904","id":"PMC_38834904","title":"Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway.","date":"2024","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38834904","citation_count":5,"is_preprint":false},{"pmid":"35278209","id":"PMC_35278209","title":"Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35278209","citation_count":5,"is_preprint":false},{"pmid":"36937047","id":"PMC_36937047","title":"Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36937047","citation_count":4,"is_preprint":false},{"pmid":"38995776","id":"PMC_38995776","title":"Screening Targets and Therapeutic Drugs for Alzheimer's Disease Based on Deep Learning Model and Molecular Docking.","date":"2024","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/38995776","citation_count":3,"is_preprint":false},{"pmid":"34788174","id":"PMC_34788174","title":"PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.","date":"2021","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/34788174","citation_count":3,"is_preprint":false},{"pmid":"37960721","id":"PMC_37960721","title":"Identification and verification of atrial fibrillation hub genes caused by primary mitral regurgitation.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37960721","citation_count":3,"is_preprint":false},{"pmid":"38110787","id":"PMC_38110787","title":"Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A.","date":"2023","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38110787","citation_count":2,"is_preprint":false},{"pmid":"40442258","id":"PMC_40442258","title":"The involvement of the synaptic vesicle cycle in homocysteine induced neurotoxicity in vitro and in vivo.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40442258","citation_count":2,"is_preprint":false},{"pmid":"40088508","id":"PMC_40088508","title":"Genetic Epilepsies With Onset in Infancy and Toddlerhood: A Prospective Single-Center Study in India.","date":"2025","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40088508","citation_count":1,"is_preprint":false},{"pmid":"40991843","id":"PMC_40991843","title":"Metabolic and Inflammatory Stimuli Impact Vascular Circulation and Cell Proliferation Processes in the Amygdala.","date":"2025","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/40991843","citation_count":1,"is_preprint":false},{"pmid":"41188235","id":"PMC_41188235","title":"Gain of Alternative Allele Expression of LINC02449 at rs149707223 in Schizophrenia and Bipolar Disorder: Inducing Synaptic Transmission and Behavioral Deficits in Mice.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41188235","citation_count":1,"is_preprint":false},{"pmid":"40766759","id":"PMC_40766759","title":"Therapeutic effects and mechanism analysis of Paeonia lactiflora extract (PLE) in menopausal rats with hot flashes.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40766759","citation_count":1,"is_preprint":false},{"pmid":"41863379","id":"PMC_41863379","title":"Riluzole Restores Circuit and Behavioral Function Altered by Allele-Specific Expression-Mediated LINC02449-CPLX1 Dysregulation.","date":"2026","source":"Schizophrenia bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/41863379","citation_count":0,"is_preprint":false},{"pmid":"42041567","id":"PMC_42041567","title":"Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/42041567","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35118,"output_tokens":4225,"usd":0.084364},"stage2":{"model":"claude-opus-4-6","input_tokens":7735,"output_tokens":3944,"usd":0.205912},"total_usd":0.290276,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Complexin I (CPLX1) is required at the endbulb of Held auditory synapse: in CPX I knockout mice, resting release probability at endbulb of Held synapses was reduced, synaptic transmission outlasted the stimulus (impaired synchronization), and sound onset/offset processing in the cochlear nucleus was abnormal, despite normal Ca2+-dependent exocytosis in inner hair cells and normal sound encoding in the cochlea.\",\n      \"method\": \"Cplx1 knockout mice, auditory brainstem responses, in vitro electrophysiology (patch-clamp), in vivo single-unit recordings, computational modeling\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and electrophysiological phenotype, multiple orthogonal methods, replicated in vivo and in vitro\",\n      \"pmids\": [\"19553439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CPLX1 is essential for normal motor function, exploratory behavior, and emotional reactivity in mice: Cplx1 knockout mice develop severe ataxia (in absence of cerebellar degeneration), profound deficits in motor coordination, dystonia, resting tremor, impaired grooming/rearing, reduced exploration, and deficits in emotional reactivity.\",\n      \"method\": \"Cplx1 knockout mice, behavioral battery (rotarod, gait analysis, open field, swim test, neuromuscular strength tests)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple well-defined behavioral/motor phenotypes across multiple paradigms\",\n      \"pmids\": [\"16000319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CPLX1 is required for normal social behavior: Cplx1 knockout mice fail to show preference for social novelty and lack normal aggressive behavior in resident-intruder paradigm, despite normal olfactory discrimination, indicating a specific role for CPLX1 in social interaction circuitry.\",\n      \"method\": \"Cplx1 knockout mice, social transmission of food preference, resident-intruder paradigm, social novelty preference, two-choice swim tank cognitive testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific behavioral phenotypes and appropriate controls ruling out cognitive or olfactory confounds\",\n      \"pmids\": [\"17652102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CPLX1 is required for normal early postnatal motor development: Cplx1 knockout mice develop ataxia by postnatal day 7 and show marked deficits in postural skills and complex movement by P21.\",\n      \"method\": \"Cplx1 knockout mice, longitudinal developmental behavioral assessment (postural skills, complex movement tasks)\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with temporally defined developmental phenotype\",\n      \"pmids\": [\"17188502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPLX1 serves dual facilitating and clamping functions at the calyx of Held synapse: genetic ablation of Cplx1 causes reduced spontaneous and evoked transmission (decreased release probability, partly due to less tight Ca2+ channel–docked SV coupling) and excessive asynchronous release after stimulation, without altering action potential waveforms, Ca2+ influx, readily releasable pool size, or quantal size.\",\n      \"method\": \"Cplx1 knockout mice, calyx of Held patch-clamp electrophysiology (evoked and spontaneous EPSCs, Ca2+ channel–SV coupling analysis), electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — native synapse preparation, multiple electrophysiological parameters, EM, rigorous controls\",\n      \"pmids\": [\"26019341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CPLX1 controls Ca2+-stimulated exocytosis in pancreatic beta-cells: overexpression or siRNA-mediated knockdown of CPLX1 strongly impairs glucose-, leucine-, and KCl-stimulated insulin secretion, particularly in the early secretory phase. CPLX1 expression in beta-cells is controlled by a neuron restrictive silencer element (NRSE) bound by the transcriptional repressor REST.\",\n      \"method\": \"siRNA knockdown and overexpression in insulin-secreting cell lines and primary islets, secretion assays (glucose, leucine, KCl stimulation), REST binding to NRSE by EMSA/reporter assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (KD and OE) with defined secretory phenotype and transcriptional mechanism\",\n      \"pmids\": [\"15126625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-137 directly targets CPLX1 (along with Nsf and Syt1) in presynaptic neurons: miR-137 gain of function downregulates CPLX1 protein, leading to impaired vesicle release, changes in synaptic vesicle pool distribution, impaired mossy fiber LTP, and hippocampus-dependent memory deficits.\",\n      \"method\": \"Human iPSC-derived neurons with minor alleles of MIR137 SNPs, miR-137 overexpression/sequestration in vivo and in vitro, synaptic vesicle pool analysis (EM), LTP recordings, behavioral tests\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function and rescue experiments in both human neurons and in vivo mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"26005852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PGC-1α is required for transcriptional regulation of CPLX1 in parvalbumin-positive interneurons: conditional deletion of PGC-1α in PV+ neurons decreases Cplx1 transcript, promotes asynchronous GABA release, and impairs long-term memory.\",\n      \"method\": \"PV-specific conditional PGC-1α knockout mice, qRT-PCR, electrophysiology (asynchronous GABA release), behavioral memory tests, microarray in PGC-1α overexpressing neuroblastoma cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific conditional KO with transcriptional, electrophysiological, and behavioral phenotypes\",\n      \"pmids\": [\"25339750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CPLX1 is enriched in SNARE complexes in schizophrenia orbitofrontal cortex: immunoprecipitation of SNAP25 showed ~2-fold enrichment of CPLX1 (along with syntaxin and Munc18-1) in schizophrenia OFC; blue-native PAGE identified an upregulated 200-kDa SNARE-CPLX1 species and downregulated 550-kDa CPLX1-containing oligomers in schizophrenia.\",\n      \"method\": \"Co-immunoprecipitation (SNAP25 pulldown), blue-native PAGE, two-cohort postmortem human brain samples\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and native PAGE in two independent human cohorts, but postmortem tissue without functional manipulation\",\n      \"pmids\": [\"25662103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Frontal CPLX1/CPLX2 ratio in 500-kDa heteromeric species (representing inhibitory/excitatory input balance) is associated with cognitive function and rate of cognitive decline in aging, independent of neuropathology and synapse density; reconstitution assays with recombinant SNARE proteins confirmed complex formation.\",\n      \"method\": \"Blue-native gel electrophoresis of postmortem human frontal and temporal cortex, reconstitution assays with recombinant proteins, multivariate analyses in longitudinal aging cohort (MAP)\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — native PAGE with reconstitution, but associative human postmortem data without direct functional manipulation\",\n      \"pmids\": [\"29496544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPLX1 expression is regulated by PGC-1α in cerebellar Purkinje cells: PGC-1α knockout mice show reduced Cplx1 transcript in cerebellum, Purkinje cell loss by 6 weeks, and a 50% reduction in Purkinje cell spike rate; 50% of cerebellar PGC-1α expression is attributable to PV+ neurons.\",\n      \"method\": \"PGC-1α knockout mice, PV-specific conditional knockout, qRT-PCR, stereological cell counts, in vivo electrophysiology (Purkinje cell spike rate)\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — global and conditional KO with defined electrophysiological and histological phenotypes\",\n      \"pmids\": [\"25610371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPLX1 knockout rats exhibit ataxia, dystonia, exploratory and movement deficits, increased anxiety, sensory deficits, decreased dendritic branching in spinal motor neurons, and abnormal stomach/intestine histomorphology leading to early death, establishing CPLX1 as required for normal motor neuron morphology and gastrointestinal function.\",\n      \"method\": \"CRISPR/Cas9 Cplx1 knockout rats, behavioral battery, Nissl staining, HE staining, Golgi staining of spinal motor neurons\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in second species with direct histological evidence of dendritic and visceral phenotypes\",\n      \"pmids\": [\"31875236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of CPX1/CPLX1 in the nigrostriatal pathway is confirmed in Cplx1-null mice: nigrostriatal pathway is compromised in Cplx1-null mice, supporting CPLX1's functional role in dopaminergic neurotransmission.\",\n      \"method\": \"Cplx1-null mice, verification of nigrostriatal pathway deficit (used as proof of principle in PD candidate gene study)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo validation in KO mice but limited mechanistic detail reported in abstract\",\n      \"pmids\": [\"29499164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPLX1 expressed in parvalbumin-positive neurons facilitates neurotransmitter release to enhance ultrasound neurotransmission: microbat PV+ neurons highly express CPLX1; perturbation of Cplx1 specifically in PV+ neurons impairs ultrasound perception in mouse auditory cortex; CPLX1 functions throughout the auditory pathway in echolocating microbats.\",\n      \"method\": \"Single-nucleus RNA-seq atlas (microbat vs megabat), AAV-mediated Cplx1 perturbation in mouse PV+ neurons, ultrasound perception behavioral assays, silencing of PV+ neurons\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific in vivo perturbation with defined behavioral phenotype, cross-species comparison with functional validation\",\n      \"pmids\": [\"38834904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LINC02449-G allele overexpression upregulates CPLX1 in the mPFC, enhancing excitatory synaptic transmission in the mPFC-NAc circuit and causing social deficits and repetitive behaviors; riluzole normalizes elevated Cplx1 expression and rescues both behavioral and electrophysiological abnormalities.\",\n      \"method\": \"AAV-mediated mPFC LINC02449-G overexpression in mice, whole-cell patch-clamp (mEPSC in NAc neurons), behavioral assays (social interaction, grooming, marble-burying), riluzole pharmacological rescue\",\n      \"journal\": \"Nature communications / Schizophrenia bulletin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — directional circuit manipulation with electrophysiology, behavior, and pharmacological rescue across two studies\",\n      \"pmids\": [\"41188235\", \"41863379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGC-1α-specific knockout in PV+ neurons blocks activity-dependent regulation of CPLX1 (and SYT2), reduces the intensity of preictal discharges, and slows ictogenesis, indicating CPLX1 in PV+ interneurons contributes to seizure generation dynamics.\",\n      \"method\": \"PV-specific PGC-1α conditional knockout mice, 0 Mg2+ ictogenic brain slice model, multi-electrode array recordings, PV interneuron and pyramidal cell firing rate analysis\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with electrophysiological phenotype, but CPLX1 role is inferred downstream of PGC-1α manipulation\",\n      \"pmids\": [\"34788174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The conserved SNARE-binding domain of complexin (Cplx3, a ribbon-synapse-specific paralogue) interferes with the SNARE complex to prevent spontaneous fusion and facilitate evoked release at ribbon synapses; an inhibitory peptide of this domain increased spontaneous SV fusion, depleted reserve SVs, and reduced Ca2+-evoked fusion — establishing a dual clamp/facilitator mechanism for complexins at these synapses.\",\n      \"method\": \"Whole-cell patch-clamp capacitance measurements and FM-dye destaining in mouse retinal bipolar neuron terminals, inhibitory peptide introduction via patch pipette, electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro peptide interference at native synapse with direct fusion readout, but uses Cplx3 not Cplx1; establishes shared mechanism for the complexin family\",\n      \"pmids\": [\"25740533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPLX1 (Complexin I) is a presynaptic protein that binds the SNARE complex and serves dual functions: it stabilizes newly primed synaptic vesicles (clamping function, preventing premature fusion) and facilitates rapid Ca2+-triggered exocytosis; loss of CPLX1 reduces release probability and tight Ca2+-channel–vesicle coupling while causing excessive asynchronous release, resulting in profound ataxia, social and motor deficits in vivo, and its transcription is regulated by PGC-1α via NRF-1 specifically in parvalbumin-positive interneurons, where it supports synchronous GABAergic neurotransmission.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CPLX1 (Complexin I) is a presynaptic SNARE-complex-binding protein that exerts dual control over neurotransmitter release: it clamps spontaneous vesicle fusion to prevent premature exocytosis and simultaneously facilitates rapid Ca²⁺-triggered synchronous release, with its loss reducing release probability, loosening Ca²⁺-channel–vesicle coupling, and promoting excessive asynchronous release [PMID:26019341, PMID:25740533]. CPLX1 is prominently expressed in parvalbumin-positive (PV+) interneurons, where its transcription is driven by PGC-1α via NRF-1, and its depletion impairs synchronous GABAergic transmission, contributes to seizure dynamics, and disrupts long-term memory [PMID:25339750, PMID:25610371, PMID:34788174]. Genetic ablation of CPLX1 in mice and rats produces severe early-onset ataxia, dystonia, social behavior deficits, reduced dendritic branching in motor neurons, gastrointestinal dysfunction, and compromised nigrostriatal dopaminergic signaling, while circuit-level overexpression in the medial prefrontal cortex enhances excitatory transmission and causes social deficits and repetitive behaviors rescuable by riluzole [PMID:16000319, PMID:31875236, PMID:41188235]. Beyond neurons, CPLX1 regulates Ca²⁺-stimulated insulin secretion in pancreatic β-cells, where its expression is controlled by REST via a neuron-restrictive silencer element [PMID:15126625].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that CPLX1 functions outside neurons — in pancreatic β-cells it controls Ca²⁺-stimulated insulin secretion, and its expression is transcriptionally repressed by REST via an NRSE, revealing tissue-specific regulation of this presynaptic protein.\",\n      \"evidence\": \"siRNA knockdown and overexpression in β-cell lines/primary islets with secretion assays; EMSA and reporter assays for REST–NRSE binding\",\n      \"pmids\": [\"15126625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which both overexpression and knockdown impair secretion is unclear\", \"Whether CPLX1 interacts with the same SNARE partners in β-cells as in neurons not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that CPLX1 loss causes severe neurological phenotypes — Cplx1 KO mice develop early ataxia, dystonia, tremor, and motor coordination deficits without cerebellar degeneration, establishing CPLX1 as essential for motor circuit function in vivo.\",\n      \"evidence\": \"Cplx1 knockout mice assessed with comprehensive behavioral battery (rotarod, gait analysis, open field, swim test)\",\n      \"pmids\": [\"16000319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic mechanism underlying motor phenotypes not yet identified\", \"Whether motor deficits reflect cerebellar, spinal, or distributed circuit dysfunction not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the developmental onset of CPLX1 dependence — ataxia appears by postnatal day 7, indicating CPLX1 is required during the critical period of motor circuit maturation.\",\n      \"evidence\": \"Longitudinal developmental behavioral assessment in Cplx1 KO mice from P7 to P21\",\n      \"pmids\": [\"17188502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether early ataxia reflects a developmental versus maintenance role is unresolved\", \"Cell types responsible for the early phenotype not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extending CPLX1's behavioral role beyond motor function — KO mice lack social novelty preference and normal aggression with intact olfaction, implicating CPLX1 in social circuit neurotransmission specifically.\",\n      \"evidence\": \"Cplx1 KO mice tested in social novelty preference, resident-intruder aggression, and olfactory discrimination assays\",\n      \"pmids\": [\"17652102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neural circuits and transmitter systems mediating the social deficits not mapped\", \"Whether social deficits are secondary to motor impairment not fully excluded\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing CPLX1's synapse-level mechanism in an identified central synapse — at the endbulb of Held, CPLX1 loss reduces release probability and desynchronizes transmission while cochlear encoding remains normal, localizing the defect to central synaptic release.\",\n      \"evidence\": \"Patch-clamp electrophysiology, in vivo single-unit recordings, and auditory brainstem responses in Cplx1 KO mice\",\n      \"pmids\": [\"19553439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reduced release probability reflects a priming, docking, or Ca²⁺-coupling defect not distinguished\", \"Compensatory changes by other complexin paralogues not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a transcriptional pathway controlling CPLX1 in inhibitory interneurons — PGC-1α in PV+ neurons is required for CPLX1 expression, and its conditional loss phenocopies CPLX1 deficiency with asynchronous GABA release and memory impairment, linking mitochondrial transcriptional coactivation to presynaptic vesicle release control.\",\n      \"evidence\": \"PV-specific conditional PGC-1α knockout mice with qRT-PCR, electrophysiology (asynchronous GABA release), and behavioral memory tests\",\n      \"pmids\": [\"25339750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PGC-1α acts on the CPLX1 promoter directly or via NRF-1 was established elsewhere but ChIP at native locus not shown\", \"Contribution of other PGC-1α targets (e.g., SYT2) to the phenotype not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving the dual clamp/facilitator mechanism at a mammalian central synapse — at the calyx of Held, CPLX1 deletion reduces evoked release probability partly through loosened Ca²⁺-channel–vesicle coupling and causes excessive asynchronous release, without altering vesicle pool size, quantal size, or Ca²⁺ influx, establishing CPLX1 as a fusion clamp and synchronous release facilitator simultaneously.\",\n      \"evidence\": \"Calyx of Held patch-clamp electrophysiology and electron microscopy in Cplx1 KO mice\",\n      \"pmids\": [\"26019341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how CPLX1 tightens Ca²⁺ channel–vesicle coupling not determined\", \"Whether the dual function involves distinct CPLX1 domains at this synapse not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending PGC-1α–CPLX1 regulation to cerebellar Purkinje cells — PGC-1α KO reduces CPLX1 in cerebellum and causes Purkinje cell loss and reduced spike rate, providing a mechanistic link to the ataxia phenotype of CPLX1 loss.\",\n      \"evidence\": \"PGC-1α global and PV-conditional KO mice, qRT-PCR, stereological Purkinje cell counts, in vivo electrophysiology\",\n      \"pmids\": [\"25610371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Purkinje cell loss is due to CPLX1 reduction specifically or other PGC-1α targets remains untested\", \"Whether CPLX1 restoration rescues the Purkinje cell phenotype not attempted\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"miR-137, a schizophrenia-associated microRNA, directly targets CPLX1 mRNA and its downregulation impairs vesicle release, mossy fiber LTP, and hippocampal memory, establishing a post-transcriptional regulatory layer for CPLX1 with psychiatric relevance.\",\n      \"evidence\": \"miR-137 gain/loss of function in human iPSC neurons and in vivo mouse hippocampus, EM vesicle pool analysis, LTP recordings, behavioral tests\",\n      \"pmids\": [\"26005852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of CPLX1 versus NSF and SYT1 (co-targets) to miR-137 phenotype not separated\", \"Whether endogenous miR-137 variation significantly modulates CPLX1 levels in human brain unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CPLX1 participates in high-molecular-weight SNARE-containing heteromeric complexes in human cortex, and the CPLX1/CPLX2 ratio in these complexes correlates with cognitive function during aging independently of neuropathology, suggesting stoichiometric balance of complexin paralogues matters for circuit performance.\",\n      \"evidence\": \"Blue-native PAGE and reconstitution assays with recombinant SNARE proteins in postmortem human cortex from a longitudinal aging cohort\",\n      \"pmids\": [\"29496544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship between CPLX1/CPLX2 ratio and cognitive decline not established\", \"Functional significance of the 500-kDa species not tested in living systems\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cross-species validation in rat confirmed CPLX1 necessity for motor function and revealed additional phenotypes — decreased dendritic branching in spinal motor neurons and abnormal gastrointestinal histomorphology, expanding CPLX1's role beyond synaptic transmission to neuronal morphology and visceral innervation.\",\n      \"evidence\": \"CRISPR/Cas9 Cplx1 KO rats with behavioral battery, Golgi staining of spinal motor neurons, GI histology\",\n      \"pmids\": [\"31875236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dendritic branching defects are cell-autonomous or secondary to activity changes unknown\", \"Mechanism of GI dysfunction (enteric neuron vs. smooth muscle) not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CPLX1 in PV+ interneurons contributes to seizure dynamics — PV-specific PGC-1α deletion, which reduces CPLX1, slows ictogenesis and reduces preictal discharge intensity, indicating that synchronous PV+ neuron output controlled by CPLX1 can paradoxically promote seizure initiation.\",\n      \"evidence\": \"PV-specific PGC-1α conditional KO, 0-Mg²⁺ ictogenic brain slice model, multi-electrode array recordings\",\n      \"pmids\": [\"34788174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CPLX1's role is inferred through PGC-1α manipulation rather than direct CPLX1 perturbation\", \"Whether CPLX1 restoration in PV+ neurons is sufficient to re-accelerate ictogenesis untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Evolutionary specialization of CPLX1 expression in PV+ neurons supports ultrasound neurotransmission — echolocating microbats selectively upregulate CPLX1 in PV+ auditory neurons, and cell-type-specific perturbation of Cplx1 in mouse PV+ neurons impairs ultrasound perception, directly linking CPLX1 to temporal precision of sensory processing.\",\n      \"evidence\": \"Cross-species single-nucleus RNA-seq, AAV-mediated Cplx1 perturbation in mouse PV+ neurons, ultrasound perception behavioral assays\",\n      \"pmids\": [\"38834904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific synaptic parameters altered by Cplx1 perturbation in auditory PV+ neurons not measured\", \"Whether CPLX1 upregulation is necessary and sufficient for echolocation ability untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Circuit-level overexpression of CPLX1 can be pathogenic — LINC02449-G-driven upregulation of CPLX1 in mPFC enhances excitatory transmission in mPFC-NAc projections and causes social deficits and repetitive behaviors, which are rescued by riluzole normalization of Cplx1, demonstrating that bidirectional CPLX1 dysregulation disrupts circuit function.\",\n      \"evidence\": \"AAV-mediated mPFC overexpression in mice, whole-cell patch-clamp (mEPSC in NAc), behavioral assays, riluzole pharmacological rescue\",\n      \"pmids\": [\"41188235\", \"41863379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether riluzole acts specifically through CPLX1 or has additional targets in this circuit not resolved\", \"LINC02449 mechanism of CPLX1 upregulation not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for CPLX1's dual clamp/facilitator function at native SNARE complexes; whether CPLX1's role in Ca²⁺-channel–vesicle coupling involves direct physical interaction with Ca²⁺ channels; and whether CPLX1 dysregulation is a causal driver (rather than correlate) of cognitive decline in aging and psychiatric disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of CPLX1 bound to the full SNARE complex at a mammalian synapse\", \"Causal relationship between CPLX1 stoichiometry in SNARE complexes and human cognitive phenotypes not demonstrated\", \"Cell-autonomous versus circuit-level contributions to motor and social phenotypes not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 7, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 5, 16]}\n    ],\n    \"complexes\": [\n      \"SNARE complex\"\n    ],\n    \"partners\": [\n      \"SNAP25\",\n      \"STX1A\",\n      \"SYT1\",\n      \"NSF\",\n      \"STXBP1\",\n      \"PPARGC1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}