Deletion of α-neurexin II results in autism-related behaviors in mice
Open accessAbstract
Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.
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?
oASD mice show increased inclusion rate of a mutually exclusive exon in Neurexin-2 (Nrxn2).
“We observed an increased inclusion rate of a mutually exclusive exon (MXE) in Neurexin-2 (Nrxn2), a presynaptic adhesion protein strongly linked to ASD (Dachtler et al., 2014; Südhof, 2008) (Figure 3F).”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Dachtler et al., 2014
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
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Andersen, C. L., Jensen, J. L., & Ørntoft, T. F. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0496 · Cited by 7,127 · see citing works
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · see citing works
Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G. (2011) · Nature · doi:10.1038/nature09965 · Cited by 1,570 · 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 · see citing works
Epidemiological Surveys of Autism and Other Pervasive Developmental Disorders: An Update
Fombonne, E. (2003) · Journal of Autism and Developmental Disorders · doi:10.1023/a:1025054610557 · Cited by 1,505 · see citing works
Synaptic Assembly of the Brain in the Absence of Neurotransmitter Secretion
Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., Toonen, R. F. G., Hammer, R. E., van den Berg, T. K., Berg, et al. (2000) · Science · doi:10.1126/science.287.5454.864 · Cited by 1,431 · see citing works
Anxiety 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 · see citing works
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421 · see citing works
Intellectual disability and its relationship to autism spectrum disorders
Matson, J. L., & Shoemaker, M. (2009) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2009.06.003 · Cited by 833 · see citing works
Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions
Simon, P. Y. R., Dupuis, R., & Costentin, J. (1994) · Behavioural Brain Research · doi:10.1016/0166-4328(94)90008-6 · Cited by 767 · see citing works
α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis
Missler, M., Zhang, W., Rohlmann, A., Kattenstroth, G., Hammer, R. E., Gottmann, K., & Südhof, T. C. (2003) · Nature · doi:10.1038/nature01755 · Cited by 699 · see citing works
Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses
Song, J.-Y., Ichtchenko, K., Südhof, T. C., & Brose, N. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.3.1100 · Cited by 696 · see citing works
Neurexin–neuroligin signaling in synapse development
Craig, A. M., & Kang, Y. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.011 · Cited by 640 · see citing works
Chubykin, A. A., Atasoy, D., Etherton, M. R., Brose, N., Kavalali, E. T., Gibson, J. R., & Südhof, T. C. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.029 · Cited by 594 · see citing works
Hata, Y., Butz, S., & Sudhof, T. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-08-02488.1996 · Cited by 553 · see citing works
Snares and Munc18 in synaptic vesicle fusion
Rizo, J., & Südhof, T. C. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn898 · Cited by 539 · see citing works
Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr212 · Cited by 537 · see citing works
MRI volumes of amygdala and hippocampus in non–mentally retarded autistic adolescents and adults
Aylward, E., Minshew, N. J., Goldstein, G., Honeycutt, N. A., Augustine, A. M., Yates, K. O., Barta, P. E., & Pearlson, G. D. (1999) · Neurology · doi:10.1212/wnl.53.9.2145 · Cited by 513 · see citing works
Characteristics and Concordance of Autism Spectrum Disorders Among 277 Twin Pairs
Rosenberg, R. E., Law, J. K., Yenokyan, G., McGready, J., Kaufmann, W. E., & Law, P. A. (2009) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpediatrics.2009.98 · Cited by 495 · see citing works
Localized enlargement of the frontal cortex in early autism
Carper, R. A., & Courchesne, E. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.11.005 · Cited by 456 · see citing works
Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior
Blundell, J., Blaiss, C. A., Etherton, M. R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M. F., Südhof, T. C., & Powell, C. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4517-09.2010 · Cited by 450 · see citing works
Etherton, 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
LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation
de Wit, J., Sylwestrak, E., O’Sullivan, M. L., Otto, S. J., Tiglio, K., Savas, J. N., Yates, J. R., Comoletti, D., Taylor, P., & Ghosh, A. (2009) · Neuron · doi:10.1016/j.neuron.2009.12.019 · Cited by 376 · see citing works
Sensorimotor gating deficits in adults with autism
Perry, W., Minassian, A., Lopez, B., Maron, L., & Lincoln, A. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.09.025 · Cited by 352 · see citing works
Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism
Horev, G., Ellegood, J., Lerch, J. P., Son, Y.-E. E., Muthuswamy, L., Vogel, H., Krieger, A. M., Buja, A., Henkelman, R. M., Wigler, M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1114042108 · Cited by 330 · see citing works
Prepulse inhibition in psychiatric disorders – Apart from schizophrenia
Kohl, S., Heekeren, K., Klosterkötter, J., & Kuhn, J. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.11.018 · Cited by 298 · see citing works
Deletions of NRXN1 (neurexin‐1) predispose to a wide spectrum of developmental disorders
Ching, M. S. L., Shen, Y., Tan, W., Jeste, S., Morrow, E. M., Chen, X., Mukaddes, N. M., Yoo, S.-Y., Hanson, E. M., Hundley, R. J., et al. (2010) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31063 · Cited by 298 · see citing works
Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia
Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafrenière, R. G., et al. (2011) · Human Genetics · doi:10.1007/s00439-011-0975-z · Cited by 286 · see citing works
Autism: Definition, Neurobiology, Screening, Diagnosis
Rapin, I., & Tuchman, R. F. (2008) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2008.07.005 · Cited by 285 · see citing works
Defects in synaptic vesicle docking in unc-18 mutants
Weimer, R. M., Richmond, J. E., Davis, W. S., Hadwiger, G., Nonet, M. L., & Jørgensen, E. M. (2003) · Nature Neuroscience · doi:10.1038/nn1118 · Cited by 262 · see citing works
Biederer, T., & Südhof, T. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000656200 · Cited by 239 · see citing works
Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size
Toonen, R. F. G., Wierda, K. D. B., Sons, M. S., de Wit, H., Cornelisse, L. N., Brussaard, A. B., Plomp, J. J., & Verhage, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608507103 · Cited by 186 · see citing works
Analysis of the Human Neurexin Genes: Alternative Splicing and the Generation of Protein Diversity
Rowen, L., Young, J. M., Birditt, B., Kaur, A., Madan, A., Philipps, D. L., Qin, S., Minx, P. J., Wilson, R. K., Hood, L., et al. (2002) · Genomics · doi:10.1006/geno.2002.6734 · Cited by 184 · see citing works
Grayton, H. M., Missler, M., Collier, D. A., & Fernandes, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067114 · Cited by 181 · see citing works
Grootjans, J. J., Reekmans, G., Ceulemans, H., & David, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002459200 · Cited by 170 · see citing works
Analysis of four neuroligin genes as candidates for autism
Ylisaukko‐oja, T., Rehnström, K., Auranen, M., Vanhala, R., Alén, R., Kempas, E., Ellonen, P., Turunen, J. A., Makkonen, I., Riikonen, R., et al. (2005) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201474 · Cited by 157 · see citing works
Belzung, C., & Berton, F. (1997) · Behavioural Pharmacology · doi:10.1097/00008877-199711000-00012 · Cited by 114 · see citing works
Genes associated with autism spectrum disorder
Li, X., Zou, H., & Brown, W. T. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2012.05.017 · Cited by 102 · see citing works
The role of neurexins in schizophrenia and autistic spectrum disorder
Reichelt, A. C., Rodgers, R. J., & Clapcote, S. J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.024 · Cited by 101 · see citing works
Self-citationDeletion of α‐neurexins does not cause a major impairment of axonal pathfinding or synapse formation
Dudanova, I., Tabuchi, K., Rohlmann, A., Südhof, T. C., & Missler, M. (2007) · Journal of Comparative Neurology · doi:10.1002/cne.21305 · Cited by 98 · see citing works
Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J mice
Baarendse, P. J. J., van Grootheest, G., Jansen, R. F., Pieneman, A. W., Ögren, S. O., Verhage, M., & Stiedl, O. (2007) · Hippocampus · doi:10.1002/hipo.20356 · Cited by 88 · see citing works
Features of the Genetically Defined Anxiety in Mice
Avgustinovich, D. F., Lipina, T. V., Bondar, N. P., Alekseyenko, O. V., & Kudryavtseva, N. N. (2000) · Behavior Genetics · doi:10.1023/a:1001999020138 · Cited by 81 · see citing works
Paré, W. P., Tejani‐Butt, S. M., & Kluczynski, J. (2001) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(01)00204-4 · Cited by 65 · see citing works
Transcriptome to proteome and back to genome
Muers, M. R. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3037 · Cited by 58 · see citing works
South, M., Dana, J., White, S. E., & Crowley, M. J. (2010) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-010-1021-z · Cited by 57 · see citing works
Oranje, B., Lahuis, B., van Engeland, H., van der Gaag, R. J., & Kemner, C. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.10.014 · Cited by 47 · see citing works
Mohrmann, I., Gillessen‐Kaesbach, G., Siebert, R., Caliebe, A., & Hellenbroich, Y. (2011) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2011.04.006 · Cited by 43 · see citing works
A de novo germline mutation in MYH7 causes a progressive dominant myopathy in pigs
Murgiano, L., Tammen, I., Harlizius, B., & Drögemüller, C. (2012) · BMC Genetics · doi:10.1186/1471-2156-13-99 · Cited by 38 · see citing works
Hager, T., Maroteaux, G., du Pont, P., Julsing, J. R., van der Vliet, R., & Stiedl, O. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.11.033 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Sharon, G., Cruz, N. J., Kang, D.-W., Gandal, M. J., Wang, B., Kim, Y.-M., Zink, E. M., Casey, C. P., Taylor, B. C., Lane, C. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.004 · Cited by 1,182 · see citing works
Gabriele, M., Vulto-van Silfhout, A. T., Germain, P.-L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.05.006 · Cited by 163 · see citing works
Howell, B. W., & Smith, K. M. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2018.11.019 · Cited by 35 · see citing works
Granon, S., Faure, A., Chauveau, F., Cressant, A., & Ey, E. (2018) · Handbook of Behavioral Neuroscience · doi:10.1016/b978-0-12-809600-0.00040-8 · Cited by 33 · 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
- Authors
- Dachtler, J., Glasper, J., Cohen, R. N., Ivorra, J. L., Swiffen, D. J., Jackson, A. J., Harte, M. K., Rodgers, R. J., & Clapcote, S. J.
- Affiliations
- University of Leeds (GB)
- University of Manchester (GB)
- Corresponding author
- Dachtler, J
- Venue
- Translational Psychiatry
- Published
- 2014-11-25
- Volume
- 4
- Issue
- 11
- Pages
- e484-e484
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC4259993
- OpenAlex
- W2119747299
- Cited by
- 84
- References
- 52
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 10 · 2016: 6 · 2015: 8 · 2013: 1
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- 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
- Wellcome Trust
- International Seafood Sustainability Foundation
- British Pharmacological Society
- University of Leeds
- Medical Research Council (G0900625)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, sociability, social memory, anxiety-like behavior, Munc18-1, STXBP1, hippocampus, frontal cortex, synaptic adhesion proteins
- MeSH terms
- Animals, Anxiety, Autistic Disorder, Avoidance Learning, Behavior, Animal, Cerebral Cortex, Hippocampus, Mice, Inbred C57BL, Nerve Tissue Proteins, Synaptic Transmission, Social Behavior, Mice, Knockout, Mice, Prepulse Inhibition
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
