Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Autism
Published in: Molecular Autism 1/2015

Open Access 01-12-2015 | Research

A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice

Authors: Emma L. Burrows, Liliana Laskaris, Lynn Koyama, Leonid Churilov, Joel C. Bornstein, Elisa L. Hill-Yardin, Anthony J. Hannan

Published in: Molecular Autism | Issue 1/2015

Login to get access

Abstract

Background

Aggression is common in patients with autism spectrum disorders (ASD) along with the core symptoms of impairments in social communication and repetitive behavior. Risperidone, an atypical antipsychotic, is widely used to treat aggression in ASD. In order to understand the neurobiological underpinnings of these challenging behaviors, a thorough characterisation of behavioral endophenotypes in animal models is required.

Methods

We investigated aggression in mice containing the ASD-associated R451C (arginine to cysteine residue 451 substitution) mutation in neuroligin-3 (NL3). Furthermore, we sought to verify social interaction impairments and assess olfaction, anxiety, and repetitive and restrictive behavior in NL3R451C mutant mice.

Results

We show a pronounced elevation in aggressive behavior in NL3R451C mutant mice. Treatment with risperidone reduced this aggression to wild-type (WT) levels. Juvenile and adult social interactions were also investigated, and subtle differences in initiation of interaction were seen in juvenile NL3R451C mice. No genotype differences in olfactory discrimination or anxiety were observed indicating that aggression was not dependent on altered olfaction, stress response, or social preference. We also describe repetitive behavior in NL3R451C mice as assessed by a clinically relevant object exploration task.

Conclusions

The presence of aberrant aggression and other behavioral phenotypes in NL3R451C mice consistent with clinical traits strengthen face validity of this model of ASD. Furthermore, we demonstrate predictive validity in this model through the reversal of the aggressive phenotype with risperidone. This is the first demonstration that risperidone can ameliorate aggression in an animal model of ASD and will inform mechanistic and therapeutic research into the neurobiology underlying abnormal behaviors in ASD.
Appendix
Available only for authorised users
Literature
1.
APA. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
2.
Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet. 2010;19(20):4072–82.PubMedCentralCrossRefPubMed
3.
Betancur C, Sakurai T, Buxbaum JD. The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci. 2009;32(7):402–12.CrossRefPubMed
4.
An JY, Cristino AS, Zhao Q, Edson J, Williams SM, Ravine D, et al., Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach. Transl Psychiatry. 2014;4:e394.PubMedCentralCrossRefPubMed
5.
Cristino AS, Williams SM, Hawi Z, An JY, Bellgrove MA, Schwartz CE, et al. Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system. Mol Psychiatry. 2014;19(3):294–301.CrossRefPubMed
6.
7.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34(1):27–9.PubMedCentralCrossRefPubMed
8.
Ching MS, Shen Y, Tan WH, Jeste SS, Morrow EM, Chen X, et al. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(4):937–47.PubMedCentralPubMed
9.
Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007;318(5847):71–6.PubMedCentralCrossRefPubMed
10.
Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, et al. The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci. 2004;24(20):4889–93.CrossRefPubMed
11.
Etherton MR, Tabuchi K, Sharma M, Ko J, Sudhof TC. An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 2011;30(14):2908–19.PubMedCentralCrossRefPubMed
12.
Foldy C, Malenka RC, Sudhof TC. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron. 2013;78(3):498–509.PubMedCentralCrossRefPubMed
13.
Jaramillo TC, Liu S, Pettersen A, Birnbaum SG, Powell CM. Autism-related neuroligin-3 mutation alters social behavior and spatial learning. Autism Res. 2014;7(2):264–72.PubMedCentralCrossRefPubMed
14.
Etherton M, Foldy C, Sharma M, Tabuchi K, Liu X, Shamloo M, et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci U S A. 2011;108(33):13764–9.PubMedCentralCrossRefPubMed
15.
Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N, et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 2008;1(3):147–58.PubMedCentralCrossRefPubMed
16.
Argyropoulos A, Gilby KL, Hill-Yardin EL. Studying autism in rodent models: reconciling endophenotypes with comorbidities. Front Hum Neurosci. 2013;7:417.PubMedCentralCrossRefPubMed
17.
Kanne SM, Mazurek MO. Aggression in children and adolescents with ASD: prevalence and risk factors. J Autism Dev Disord. 2011;41(7):926–37.CrossRefPubMed
18.
Card NA, Little TD. Proactive and reactive aggression in childhood and adolescence: A meta-analysis of differential relations with psychosocial adjustment. Int J Behav Dev. 2006;30:466–80.CrossRef
19.
Sharma A, Shaw SR. Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum disorder: a meta-analysis. J Pediatr Health Care. 2012;26(4):291–9.CrossRefPubMed
20.
Aman MG, Arnold LE, McDougle CJ, Vitiello B, Scahill L, Davies M, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol. 2005;15(6):869–84.CrossRefPubMed
21.
Canitano R, Scandurra V. Risperidone in the treatment of behavioral disorders associated with autism in children and adolescents. Neuropsychiatr Dis Treat. 2008;4(4):723–30.PubMedCentralCrossRefPubMed
22.
Lemmon ME, Gregas M, Jeste SS. Risperidone use in autism spectrum disorders: a retrospective review of a clinic-referred patient population. J Child Neurol. 2011;26(4):428–32.CrossRefPubMed
23.
Miczek KA, Maxson SC, Fish EW, Faccidomo S. Aggressive behavioral phenotypes in mice. Behav Brain Res. 2001;125(1–2):167–81.CrossRefPubMed
24.
Miczek KA, Fish EW, De Bold JF. Neurosteroids, GABAA receptors, and escalated aggressive behavior. Horm Behav. 2003;44(3):242–57.CrossRefPubMed
25.
Miczek KA, Fish EW, De Bold JF, De Almeida RM. Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems. Psychopharmacology (Berl). 2002;163(3–4):434–58.CrossRef
26.
Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry. 2001;49(8):655–64.CrossRefPubMed
27.
Pearson BL, Pobbe RL, Defensor EB, Oasay L, Bolivar VJ, Blanchard DC, et al. Motor and cognitive stereotypies in the BTBR T + tf/J mouse model of autism. Genes Brain Behav. 2011;10(2):228–35.PubMedCentralCrossRefPubMed
28.
Yang M, Silverman JL, Crawley JN. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 2011;Chapter 8:Unit 8 26.PubMed
29.
Yang M, Crawley JN. Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci. 2009;Chapter 8:Unit 8 24.PubMed
30.
Velez L, Sokoloff G, Miczek KA, Palmer AA, Dulawa SC. Differences in aggressive behavior and DNA copy number variants between BALB/cJ and BALB/cByJ substrains. Behav Genet. 2010;40(2):201–10.PubMedCentralCrossRefPubMed
31.
Burrows EL, Hannan AJ. Characterizing social behavior in genetically targeted mouse models of brain disorders. Methods Mol Biol. 2013;1017:95–104.CrossRefPubMed
32.
Bespalov A, Jongen-Relo AL, van Gaalen M, Harich S, Schoemaker H, Gross G. Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. J Pharmacol Exp Ther. 2007;320(2):944–50.CrossRefPubMed
33.
Rogoz Z. Effects of co-treatment with mirtazapine and low doses of risperidone on immobility time in the forced swimming test in mice. Pharmacol Rep. 2010;62(6):1191–6.CrossRefPubMed
34.
Rogoz Z, Kabzinski M. Enhancement of the anti-immobility action of antidepressants by risperidone in the forced swimming test in mice. Pharmacol Rep. 2011;63(6):1533–8.CrossRefPubMed
35.
Siuciak JA, McCarthy SA, Martin AN, Chapin DS, Stock J, Nadeau DM, et al. Disruption of the neurokinin-3 receptor (NK3) in mice leads to cognitive deficits. Psychopharmacology (Berl). 2007;194(2):185–95.CrossRef
36.
Bradford AM, Savage KM, Jones DN, Kalinichev M. Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. Psychopharmacology (Berl). 2010;212(2):155–70.CrossRef
37.
Rodriguez-Arias M, Broseta I, Aguilar MA, Minarro J. Lack of specific effects of selective D(1) and D(2) dopamine antagonists vs. risperidone on morphine-induced hyperactivity. Pharmacol Biochem Behav. 2000;66(1):189–97.CrossRefPubMed
38.
Cleves M, Gould W, Gutierrez R, Marchenko Y. An introduction to survival analysis using STATA.2nd ed. College Station, TX: StataCorp LP; 2008.
39.
Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med. 2012;4(131):131ra51.CrossRefPubMed
40.
Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med. 2011;3(103):103ra97.PubMedCentralCrossRefPubMed
41.
McDougle CJ, Scahill L, McCracken JT, Aman MG, Tierney E, Arnold LE, et al. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin N Am. 2000;9(1):201–24.PubMed
42.
McDougle CJ, Stigler KA, Erickson CA, Posey DJ. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry. 2008;69 Suppl 4:15–20.PubMed
43.
Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, et al. Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell. 2014;158(1):198–212.PubMedCentralCrossRefPubMed
44.
Ellegood J, Lerch JP, Henkelman RM. Brain abnormalities in a neuroligin3 R451C knockin mouse model associated with autism. Autism Res. 2011;4(5):368–76.CrossRefPubMed
45.
Kumar M, Duda JT, Hwang WT, Kenworthy C, Ittyerah R, Pickup S, et al. High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder. PLoS One. 2014;9(10), e109872.PubMedCentralCrossRefPubMed
46.
Di Martino A, Kelly C, Grzadzinski R, Zuo XN, Mennes M, Mairena MA, et al. Aberrant striatal functional connectivity in children with autism. Biol Psychiatry. 2011;69(9):847–56.PubMedCentralCrossRefPubMed
47.
Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E, et al. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiatry. 2005;58(3):226–32.CrossRefPubMed
48.
Langen M, Schnack HG, Nederveen H, Bos D, Lahuis BE, de Jonge MV, et al. Changes in the developmental trajectories of striatum in autism. Biol Psychiatry. 2009;66(4):327–33.CrossRefPubMed
49.
Jin HM, Shrestha Muna S, Bagalkot TR, Cui Y, Yadav BK, Chung YC. The effects of social defeat on behavior and dopaminergic markers in mice. Neuroscience. 2015;288:167–77.CrossRefPubMed
50.
Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008;13(1):27–35.CrossRefPubMed
51.
Sakaue M, Ago Y, Sowa C, Sakamoto Y, Nishihara B, Koyama Y, et al. Modulation by 5-HT2A receptors of aggressive behavior in isolated mice. Jpn J Pharmacol. 2002;89(1):89–92.CrossRefPubMed
52.
White SM, Kucharik RF, Moyer JA. Effects of serotonergic agents on isolation-induced aggression. Pharmacol Biochem Behav. 1991;39(3):729–36.CrossRefPubMed
53.
Couppis M, Kennedy C. The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice. Psychopharmacology. 2008;197(3):449–56.CrossRefPubMed
54.
Schwartzer JJ, Melloni RHJ. Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors. Behav Neurosci. 2010;124(5):645–55.PubMedCentralCrossRefPubMed
Metadata
Title
A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice
Authors
Emma L. Burrows
Liliana Laskaris
Lynn Koyama
Leonid Churilov
Joel C. Bornstein
Elisa L. Hill-Yardin
Anthony J. Hannan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2015
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-015-0055-7

Other articles of this Issue 1/2015

Molecular Autism 1/2015 Go to the issue

Research

Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice

Research

Regional brain volume differences between males with and without autism spectrum disorder are highly age-dependent

Research

Atypical emotional anticipation in high-functioning autism

Research

Is impaired joint attention present in non-clinical individuals with high autistic traits?

Erratum

Erratum to: NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder

Research

NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder