Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.
Open accessAbstract
The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding α-neurexin I (Nrxn1α) and α-neurexin II (Nrxn2α), in individuals with autism spectrum disorders and schizophrenia. However, the link between α-neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1α or Nrxn2α. We found that in a test of social approach, Nrxn1α HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1α HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2α HET mice. Nrxn2α HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1α and Nrxn2α genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of α-neurexin I and α-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In mice, only mild phenotypes and varying results have been described in the social spectrum after nrxn1 ablation.
“but in the social spectrum, only mild phenotypes and varying results have been described (Grayton et al. 2013, Rabaneda et al. 2014, Dachtler et al. 2015; Armstrong et al. 2020).”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Dachtler et al. 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Meaney, M. J. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1161 · Cited by 2,708 · see citing works
Moy, S. S., Nadler, J. J., Perez, A., Barbaro, R. P., Johns, J. M., Magnuson, T. R., Piven, J., & Crawley, J. N. (2004) · Genes, Brain and Behavior · doi:10.1111/j.1601-1848.2004.00076.x · Cited by 1,545 · cited 5× · see citing works
“However, extensive validation using the same apparatus found no biasing effect of using male conspecifics; specifically there were “no confounding sexual or aggressive behaviors, because the strangers were contained within the wire cages” (Moy et al., 2004).”
BackgroundMethodInfluentialAnxiety in children and adolescents with autism spectrum disorders
White, S. W., Oswald, D., Ollendick, T., & Scahill, L. (2009) · Clinical Psychology Review · doi:10.1016/j.cpr.2009.01.003 · Cited by 1,427 · cited 2× · see citing works
“It has been noted that a subset of autistic patients have comorbid anxiety disorders (White et al., 2009), and a strong anxiety-like phenotype has been observed in Nrxn2 KO mice (Dachtler et al.”
BackgroundEtherton, M. R., Blaiss, C. A., Powell, C. M., & Südhof, T. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910297106 · Cited by 447 · see citing works
Behavioral phenotyping strategies for mutant mice
Crawley, J. N. (2008) · Neuron · doi:10.1016/j.neuron.2008.03.001 · Cited by 439 · see citing works
Flagged first, then by citations
Research works printed but not linked: 43
- Aylward E., Walker E., & Bettes B. (1984). Intelligence in schizophrenia: Meta-analysis of the research. Schizophrenia Bulletin, 10, 430– 459. 10.1093/schbul/10.3.430 6382590 · DOI
- Baarendse P. J., van Grootheest G., Jansen R. F., Pieneman A. W., Ogren S. O., Verhage M., & Stiedl O. (2008). Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J mice. Hippocampus, 18, 11– 19. 10.1002/hipo.20356 17696168 · DOI
- Biederer T., & Südhof T. C. (2000). Mints as adaptors. Direct binding to neurexins and recruitment of munc18. The Journal of Biological Chemistry, 275, 39803– 39806. 10.1074/jbc.C000656200 11036064 · DOI
- Blundell J., Blaiss C. A., Etherton M. R., Espinosa F., Tabuchi K., Walz C.,... Powell C. M. (2010). Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. The Journal of Neuroscience, 30, 2115– 2129. 10.1523/JNEUROSCI.4517-09.2010 20147539 PMC2824441 · DOI · Paper page
- Born G., Grayton H. M., Langhorst H., Dudanova I., Rohlmann A., Woodward B. W.,... Missler M. (2015). Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors. Frontiers in Synaptic Neuroscience, 7, 3 10.3389/fnsyn.2015.00003 25745399 PMC4333794 · DOI
- Braff D. L., Grillon C., & Geyer M. A. (1992). Gating and habituation of the startle reflex in schizophrenic patients. Archives of General Psychiatry, 49, 206– 215. 10.1001/archpsyc.1992.01820030038005 1567275 · DOI
- Cardno A. G., & Gottesman I. I. (2000). Twin studies of schizophrenia: From bow-and-arrow concordances to star wars Mx and functional genomics. [Review]. American Journal of Medical Genetics, 97, 12– 17. 10.1002/(SICI)1096-8628(200021)97:1<12::AID-AJMG3>3.0.CO;2-U 10813800 · DOI · Paper page
- Ching M. S., Shen Y., Tan W. H., Jeste S. S., Morrow E. M., Chen X.,... Wu B. L., & the Children’s Hospital Boston Genotype Phenotype Study Group (2010). Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153B, 937– 947. PMC3001124 20468056
- Chubykin A. A., Atasoy D., Etherton M. R., Brose N., Kavalali E. T., Gibson J. R., & Südhof T. C. (2007). Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron, 54, 919– 931. 10.1016/j.neuron.2007.05.029 17582332 PMC3738748 · DOI · Paper page
- Clapcote S. J., Lipina T. V., Millar J. K., Mackie S., Christie S., Ogawa F.,... Roder J. C. (2007). Behavioral phenotypes of Disc1 missense mutations in mice. Neuron, 54, 387– 402. 10.1016/j.neuron.2007.04.015 17481393 · DOI · Paper page
- Craig A. M., & Kang Y. (2007). Neurexin-neuroligin signaling in synapse development. Current Opinion in Neurobiology, 17, 43– 52. 10.1016/j.conb.2007.01.011 17275284 PMC2820508 · DOI
- Crawley J. N., & Paylor R. (1997). A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. [Review]. Hormones and Behavior, 31, 197– 211. 10.1006/hbeh.1997.1382 9213134 · DOI
- Dabell M. P., Rosenfeld J. A., Bader P., Escobar L. F., El-Khechen D., Vallee S. E.,... Shaffer L. G. (2013). Investigation of NRXN1 deletions: Clinical and molecular characterization. American Journal of Medical Genetics: Part A, 161A, 717– 731. 23495017
- Dachtler J., Glasper J., Cohen R. N., Ivorra J. L., Swiffen D. J., Jackson A. J.,... Clapcote S. J. (2014). Deletion of α-neurexin II results in autism-related behaviors in mice. Translational Psychiatry, 4, 10.1038/tp.2014.123 PMC4259993 25423136 · DOI · Paper page
- Deacon R. M. (2006). Assessing nest building in mice. Nature Protocols, 1, 1117– 1119. 10.1038/nprot.2006.170 17406392 · DOI
- de Wit J., Sylwestrak E., O’Sullivan M. L., Otto S., Tiglio K., Savas J. N.,... Ghosh A. (2009). LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron, 64, 799– 806. 10.1016/j.neuron.2009.12.019 20064388 PMC2829666 · DOI
- Duong L., Klitten L. L., Møller R. S., Ingason A., Jakobsen K. D., Skjødt C.,... Tommerup N. (2012). Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 159B, 354– 358. 10.1002/ajmg.b.32036 22337556 · DOI
- Fombonne E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: An update. Journal of Autism and Developmental Disorders, 33, 365– 382. 10.1023/A:1025054610557 12959416 · DOI · Paper page
- Friedman J. M., Baross A., Delaney A. D., Ally A., Arbour L., Armstrong L.,... Marra M. A. (2006). Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. American Journal of Human Genetics, 79, 500– 513. 10.1086/507471 16909388 PMC1559542 · DOI
- Gauthier J., Siddiqui T. J., Huashan P., Yokomaku D., Hamdan F. F., Champagne N.,... Rouleau G. A. (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human Genetics, 130, 563– 573. 10.1007/s00439-011-0975-z 21424692 PMC3204930 · DOI · Paper page
- Geppert M., Khvotchev M., Krasnoperov V., Goda Y., Missler M., Hammer R. E.,... Südhof T. C. (1998). Neurexin I alpha is a major alpha-latrotoxin receptor that cooperates in alpha-latrotoxin action. The Journal of Biological Chemistry, 273, 1705– 1710. 10.1074/jbc.273.3.1705 9430716 · DOI
- Grayton H. M., Missler M., Collier D. A., & Fernandes C. (2013). Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders. PLoS ONE, 8, 10.1371/journal.pone.0067114 PMC3696036 23840597 · DOI
- Hager T., Maroteaux G., Pont P., Julsing J., van Vliet R., & Stiedl O. (2014). Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice. Behavioural Brain Research, 260, 44– 52. 10.1016/j.bbr.2013.11.033 24304718 · DOI
- Harrison V., Connell L., Hayesmoore J., McParland J., Pike M. G., & Blair E. (2011). Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. [Case Reports]. American Journal of Medical Genetics: Part A, 155A, 2826– 2831. 10.1002/ajmg.a.34255 21964664 · DOI
- Hedman A. M., van Haren N. E., van Baal C. G., Kahn R. S., & Hulshoff Pol H. E. (2013). IQ change over time in schizophrenia and healthy individuals: A meta-analysis. Schizophrenia Research, 146, 201– 208. 10.1016/j.schres.2013.01.027 23490758 · DOI
- Hikida T., Jaaro-Peled H., Seshadri S., Oishi K., Hookway C., Kong S.,... Sawa A. (2007). Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proceedings of the National Academy of Sciences of the United States of America, 104, 14501– 14506. 17675407 PMC1964873
- Ichtchenko K., Nguyen T., & Südhof T. C. (1996). Structures, alternative splicing, and neurexin binding of multiple neuroligins. [Research Support, U.S. Gov’t, P. H. S.]. The Journal of Biological Chemistry, 271, 2676– 2682. 10.1074/jbc.271.5.2676 8576240 · DOI
- Kirov G., Rujescu D., Ingason A., Collier D. A., O’Donovan M. C., & Owen M. J. (2009). Neurexin 1 (NRXN1) deletions in schizophrenia. [Review]. Schizophrenia Bulletin, 35, 851– 854. 10.1093/schbul/sbp079 19675094 PMC2728827 · DOI · Paper page
- Laarakker M. C., Reinders N. R., Bruining H., Ophoff R. A., & Kas M. J. (2012). Sex-dependent novelty response in neurexin-1α mutant mice. PLoS ONE, 7, 10.1371/journal.pone.0031503 PMC3278455 22348092 · DOI
- Lister R. G. (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology, 92, 180– 185. 10.1007/BF00177912 3110839 · DOI
- Missler M., Zhang W., Rohlmann A., Kattenstroth G., Hammer R. E., Gottmann K., & Südhof T. C. (2003). Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature, 423, 939– 948. 10.1038/nature01755 12827191 · DOI · Paper page
- Mohrmann I., Gillessen-Kaesbach G., Siebert R., Caliebe A., & Hellenbroich Y. (2011). A de novo 0.57 Mb microdeletion in chromosome 11q13.1 in a patient with speech problems, autistic traits, dysmorphic features and multiple endocrine neoplasia type 1. European Journal of Medical Genetics, 54, e461– e464. 10.1016/j.ejmg.2011.04.006 21600320 · DOI
- Pellow S., & File S. E. (1986). Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: A novel test of anxiety in the rat. Pharmacology Biochemistry and Behavior, 24, 525– 529. 10.1016/0091-3057(86)90552-6 2871560 · DOI
- Peripato A. C., & Cheverud J. M. (2002). Genetic influences on maternal care. American Naturalist, 160(Suppl. 6), S173– S185. 10.1086/342900 18707475 · DOI
- Perry W., Minassian A., Lopez B., Maron L., & Lincoln A. (2007). Sensorimotor gating deficits in adults with autism. Biological Psychiatry, 61, 482– 486. 10.1016/j.biopsych.2005.09.025 16460695 · DOI · Paper page
- Piskulic D., Olver J. S., Norman T. R., & Maruff P. (2007). Behavioural studies of spatial working memory dysfunction in schizophrenia: A quantitative literature review. [Review]. Psychiatry Research, 150, 111– 121. 10.1016/j.psychres.2006.03.018 17292970 · DOI
- Reichelt A. C., Rodgers R. J., & Clapcote S. J. (2012). The role of neurexins in schizophrenia and autistic spectrum disorder. Neuropharmacology, 62, 1519– 1526. 10.1016/j.neuropharm.2011.01.024 21262241 · DOI
- Ronald A., Happé F., Bolton P., Butcher L. M., Price T. S., Wheelwright S.,... Plomin R. (2006). Genetic heterogeneity between the three components of the autism spectrum: A twin study. Journal of the American Academy of Child & Adolescent Psychiatry, 45, 691– 699. 10.1097/01.chi.0000215325.13058.9d 16721319 · DOI · Paper page
- Shoji H., Toyama K., Takamiya Y., Wakana S., Gondo Y., & Miyakawa T. (2012). Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice. BMC Research Notes, 5, 108 10.1186/1756-0500-5-108 22348257 PMC3392730 · DOI
- Utine G. E., Haliloğlu G., Volkan-Salancı B., Çetinkaya A., Kiper P. O., Alanay Y.,... Alikaşifoğlu M. (2014). Etiological yield of SNP microarrays in idiopathic intellectual disability. European Journal of Paediatric Neurology, 18, 327– 337. 10.1016/j.ejpn.2014.01.004 24508361 · DOI
- Verhage M., Maia A. S., Plomp J. J., Brussaard A. B., Heeroma J. H., Vermeer H.,... Südhof T. C. (2000). Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science, 287, 864– 869. 10.1126/science.287.5454.864 10657302 · DOI
- Yang M., Silverman J. L., & Crawley J. N. (2011). Automated three-chambered social approach task for mice. Current Protocols in Neuroscience, 56, Unit 8 26 10.1002/0471142301.ns0826s56 PMC4904775 21732314 · DOI · Paper page
- Zweier C., de Jong E. K., Zweier M., Orrico A., Ousager L. B., Collins A. L.,... Rauch A. (2009). CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. American Journal of Human Genetics, 85, 655– 666. 10.1016/j.ajhg.2009.10.004 19896112 PMC2775834 · DOI · Paper page
Cited by
Sorted by citations
Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits
Südhof, T. C. (2017) · Cell · doi:10.1016/j.cell.2017.10.024 · Cited by 810 · see citing works
Richter, M., Murtaza, N., Scharrenberg, R., White, S. H., Johanns, O., Walker, S., Yuen, R. K. C., Schwanke, B., Bedürftig, B., Henis, M., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0025-5 · Cited by 169 · see citing works
Brito-Moreira, J., Lourenco, M. V., Oliveira, M. M., Ribeiro, F. C., Ledo, J. H., Diniz, L. P., Vital, J. F. S., Magdesian, M. H., Melo, H. M., Barros-Aragão, F., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.761189 · Cited by 84 · see citing works
Phenotypic spectrum of <i>NRXN1</i> mono‐ and bi‐allelic deficiency: A systematic review
Castronovo, P., Baccarin, M., Ricciardello, A., Picinelli, C., Tomaiuolo, P., Cucinotta, F., Frittoli, M., Lintas, C., Sacco, R., & Persico, A. M. (2020) · Clinical Genetics · doi:10.1111/cge.13537 · Cited by 65 · see citing works
Social behavior in prepubertal neurexin 1α deficient rats: A model of neurodevelopmental disorders.
Kight, K. E., Argue, K. J., Bumgardner, J. G., Bardhi, K., Waddell, J., & McCarthy, M. M. (2021) · Behavioral Neuroscience · doi:10.1037/bne0000482 · Cited by 17 · see citing works
Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity
Lee, A. K., Khaled, H., Chofflet, N., & Takahashi, H. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00281 · Cited by 14 · see citing works
Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia
Achterberg, E. J. M., Biemans, B., & Vanderschuren, L. J. M. J. (2025) · Psychopharmacology · doi:10.1007/s00213-024-06559-z · Cited by 9 · see citing works
“…inhibition and spatial memory, and increased grooming and motor learning (Etherton et al. 2009; Blundell et al. 2010), but in the social spectrum, only mild phenotypes and varying results have been described (Grayton et al. 2013, Rabaneda et al. 2014, Dachtler et al. 2015; Armstrong et al. 2020).”
- Authors
- Dachtler, J., Ivorra, J. L., Rowland, T. E., Lever, C., Rodgers, R. J., & Clapcote, S. J.
- Affiliations
- University of Leeds (GB)
- Durham University (GB)
- Corresponding author
- Dachtler, James
- Venue
- Behavioral Neuroscience
- Published
- 2015-12
- Volume
- 129
- Issue
- 6
- Pages
- 765-776
- ISSN
- 0735-7044 (ISSN-L)
- 1939-0084
- PMC
- PMC4655861
- OpenAlex
- W2157320870
- Cited by
- 83
- References
- 5
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 11 · 2017: 8 · 2016: 3
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Behavioral Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Durham Research Online (Durham University) (acceptedVersion, cc-by)
- Durham Research Online (Durham University) (submittedVersion, cc-by)
- Funders
- Medical Research Council (G0900625)
- Wellcome Trust
- Royal Society
- British Pharmacological Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neurexin, NRXN1, heterozygous deletion, autism spectrum disorder, schizophrenia, social memory, social approach, passive avoidance, object discrimination, cognitive impairment, anxiety, mouse model
- MeSH terms
- Animals, Anxiety, Autistic Disorder, Calcium-Binding Proteins, Cognition, Discrimination, Psychological, Female, Learning, Male, Memory, Mice, Inbred C57BL, Motor Activity, Nerve Tissue Proteins, Phenotype, Schizophrenic Psychology, Social Behavior, Sequence Deletion, Mice, Knockout, Neural Cell Adhesion Molecules
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
