Hill-Yardin EL

References (12)

Title : Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3(R451C) Mouse Model of Autism - Hosie_2024_Int.J.Mol.Sci_25_
Author(s) : Hosie S , Abo-Shaban T , Mou K , Balasuriya GK , Mohsenipour M , Alamoudi MU , Filippone RT , Belz GT , Franks AE , Bornstein JC , Nurgali K , Hill-Yardin EL
Ref : Int J Mol Sci , 25 : , 2024
Abstract : Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3(R451C) mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3(R451C) mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3(R451C) mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3(R451C) mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3(R451C) mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABA(A) antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3(R451C) p = 0.002), but not the ileum, in both wild-type and Nlgn3(R451C) mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.
ESTHER : Hosie_2024_Int.J.Mol.Sci_25_
PubMedSearch : Hosie_2024_Int.J.Mol.Sci_25_
PubMedID: 38255906
Gene_locus related to this paper: mouse-3neur

Title : Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3(R451C) Mice - Herath_2023_Biomolecules_13_
Author(s) : Herath M , Cho E , Marklund U , Franks AE , Bornstein JC , Hill-Yardin EL
Ref : Biomolecules , 13 : , 2023
Abstract : Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3(R451C) mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 beta -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.
ESTHER : Herath_2023_Biomolecules_13_
PubMedSearch : Herath_2023_Biomolecules_13_
PubMedID: 37509099

Title : Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3(R451C) mouse model of autism - Lee_2023_Sci.Rep_13_12687
Author(s) : Lee CYQ , Balasuriya GK , Herath M , Franks AE , Hill-Yardin EL
Ref : Sci Rep , 13 :12687 , 2023
Abstract : Individuals with Autism Spectrum Disorder (ASD; autism) commonly present with gastrointestinal (GI) illness in addition to core diagnostic behavioural traits. The appendix, or cecum in mice, is important for GI homeostasis via its function as a key site for fermentation and a microbial reservoir. Even so, the role of the appendix and cecum in autism-associated GI symptoms remains uninvestigated. Here, we studied mice with an autism-associated missense mutation in the post-synaptic protein neuroligin-3 (Nlgn3(R451C)), which impacts brain and enteric neuronal activity. We assessed for changes in cecal motility using a tri-cannulation video-imaging approach in ex vivo preparations from wild-type and Nlgn3(R451C) mice. We investigated cecal permeability and neurally-evoked secretion in wild-type and Nlgn3(R451C) tissues using an Ussing chamber set-up. The number of cecal patches in fresh tissue samples were assessed and key immune populations including gut macrophages and dendritic cells were visualised using immunofluorescence. Nlgn3(R451C) mice displayed accelerated cecal motor complexes and reduced cecal weight in comparison to wildtype littermates. Nlgn3(R451C) mice also demonstrated reduced neurally-evoked cecal secretion in response to the nicotinic acetylcholine receptor agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP), but permeability was unchanged. We observed an increase in the number of cecal patches in Nlgn3(R451C) mice, however the cellular morphologies of key immune populations studied were not significantly altered. We show that the R451C nervous system mutation leads to cecal dysmotility, impaired secretion, and neuro-immune alterations. Together, these results suggest that the R451C mutation disrupts the gut-brain axis with GI dysfunction in autism.
ESTHER : Lee_2023_Sci.Rep_13_12687
PubMedSearch : Lee_2023_Sci.Rep_13_12687
PubMedID: 37542090
Gene_locus related to this paper: mouse-3neur

Title : The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders - Hosie_2022_Adv.Exp.Med.Biol_1383_141
Author(s) : Hosie S , Abo-Shaban T , Lee CYQ , Matta SM , Shindler A , Gore R , Sharna SS , Herath M , Crack PJ , Franks AE , Hill-Yardin EL
Ref : Advances in Experimental Medicine & Biology , 1383 :141 , 2022
Abstract : Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3(R451C) mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3(R451C) mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3(R451C) mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.
ESTHER : Hosie_2022_Adv.Exp.Med.Biol_1383_141
PubMedSearch : Hosie_2022_Adv.Exp.Med.Biol_1383_141
PubMedID: 36587154
Gene_locus related to this paper: human-NLGN3

Title : An altered glial phenotype in the NL3(R451C) mouse model of autism - Matta_2020_Sci.Rep_10_14492
Author(s) : Matta SM , Moore Z , Walker FR , Hill-Yardin EL , Crack PJ
Ref : Sci Rep , 10 :14492 , 2020
Abstract : Autism Spectrum Disorder (ASD; autism) is a neurodevelopmental disorder characterised by deficits in social communication, and restricted and/or repetitive behaviours. While the precise pathophysiologies are unclear, increasing evidence supports a role for dysregulated neuroinflammation in the brain with potential effects on synapse function. Here, we studied characteristics of microglia and astrocytes in the Neuroligin-3 (NL3(R451C)) mouse model of autism since these cell types are involved in regulating both immune and synapse function. We observed increased microglial density in the dentate gyrus (DG) of NL3(R451C) mice without morphological differences. In contrast, WT and NL3(R451C) mice had similar astrocyte density but astrocyte branch length, the number of branch points, as well as cell radius and area were reduced in the DG of NL3(R451C) mice. Because retraction of astrocytic processes has been linked to altered synaptic transmission and dendrite formation, we assessed for regional changes in pre- and postsynaptic protein expression in the cortex, striatum and cerebellum in NL3(R451C) mice. NL3(R451C) mice showed increased striatal postsynaptic density 95 (PSD-95) protein levels and decreased cortical expression of synaptosomal-associated protein 25 (SNAP-25). These changes could contribute to dysregulated neurotransmission and cognition deficits previously reported in these mice.
ESTHER : Matta_2020_Sci.Rep_10_14492
PubMedSearch : Matta_2020_Sci.Rep_10_14492
PubMedID: 32879325

Title : Altered Caecal Neuroimmune Interactions in the Neuroligin-3(R451C) Mouse Model of Autism - Sharna_2020_Front.Cell.Neurosci_14_85
Author(s) : Sharna SS , Balasuriya GK , Hosie S , Nithianantharajah J , Franks AE , Hill-Yardin EL
Ref : Front Cell Neurosci , 14 :85 , 2020
Abstract : The intrinsic nervous system of the gut interacts with the gut-associated lymphoid tissue (GALT) via bidirectional neuroimmune interactions. The caecum is an understudied region of the gastrointestinal (GI) tract that houses a large supply of microbes and is involved in generating immune responses. The caecal patch is a lymphoid aggregate located within the caecum that regulates microbial content and immune responses. People with Autism Spectrum Disorder (ASD; autism) experience serious GI dysfunction, including inflammatory disorders, more frequently than the general population. Autism is a highly prevalent neurodevelopmental disorder defined by the presence of repetitive behavior or restricted interests, language impairment, and social deficits. Mutations in genes encoding synaptic adhesion proteins such as the R451C missense mutation in neuroligin-3 (NL3) are associated with autism and impair synaptic transmission. We previously reported that NL3(R451C) mice, a well-established model of autism, have altered enteric neurons and GI dysfunction; however, whether the autism-associated R451C mutation alters the caecal enteric nervous system and immune function is unknown. We assessed for gross anatomical changes in the caecum and quantified the proportions of caecal submucosal and myenteric neurons in wild-type and NL3(R451C) mice using immunofluorescence. In the caecal patch, we assessed total cellular density as well as the density and morphology of Iba-1 labeled macrophages to identify whether the R451C mutation affects neuro-immune interactions. NL3(R451C) mice have significantly reduced caecal weight compared to wild-type mice, irrespective of background strain. Caecal weight is also reduced in mice lacking Neuroligin-3. NL3(R451C) caecal ganglia contain more neurons overall and increased numbers of Nitric Oxide (NO) producing neurons (labeled by Nitric Oxide Synthase; NOS) per ganglion in both the submucosal and myenteric plexus. Overall caecal patch cell density was unchanged however NL3(R451C) mice have an increased density of Iba-1 labeled enteric macrophages. Macrophages in NL3(R451C) were smaller and more spherical in morphology. Here, we identify changes in both the nervous system and immune system caused by an autism-associated mutation in Nlgn3 encoding the postsynaptic cell adhesion protein, Neuroligin-3. These findings provide further insights into the potential modulation of neural and immune pathways.
ESTHER : Sharna_2020_Front.Cell.Neurosci_14_85
PubMedSearch : Sharna_2020_Front.Cell.Neurosci_14_85
PubMedID: 32327975
Gene_locus related to this paper: human-NLGN3

Title : Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin-3 knockout mouse - Leembruggen_2020_Autism.Res_13_691
Author(s) : Leembruggen AJL , Balasuriya GK , Zhang J , Schokman S , Swiderski K , Bornstein JC , Nithianantharajah J , Hill-Yardin EL
Ref : Autism Res , 13 :691 , 2020
Abstract : Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin-3 are associated with autism. Mice lacking Neuroligin-3 (Nlgn3(-/-) ) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3(-/-) mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3(-/-) mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3(-/-) mice had similar numbers of neurons expressing the pan-neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3(-/-) mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3(-/-) mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3(-/-) mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3(-/-) mice, these findings suggest that Neuroligin-3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2020, 13: 691-701. 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gut problems. Many gene mutations associated with autism affect neuronal activity. We studied mice in which the autism-associated Neuroligin-3 gene is deleted to determine whether this impacts gut neuronal numbers or motility. We found that although mutant mice had similar gut structure and numbers of neurons in all gut regions examined, they had distended colons and faster colonic muscle contractions. Further work is needed to understand how Neuroligin-3 affects neuron connectivity in the gastrointestinal tract.
ESTHER : Leembruggen_2020_Autism.Res_13_691
PubMedSearch : Leembruggen_2020_Autism.Res_13_691
PubMedID: 31002480

Title : Environmental enrichment modulates affiliative and aggressive social behaviour in the neuroligin-3 R451C mouse model of autism spectrum disorder - Burrows_2020_Pharmacol.Biochem.Behav_195_172955
Author(s) : Burrows EL , Koyama L , May C , Hill-Yardin EL , Hannan AJ
Ref : Pharmacol Biochem Behav , 195 :172955 , 2020
Abstract : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impairments in social communication and the presence of restrictive and repetitive behaviours. A mouse model expressing an autism-associated R451C mutation in the gene encoding the synaptic adhesion protein neuroligin-3 (NL3) has been extensively characterised and shows altered behaviour relevant to core traits observed in ASD. Reported impairments in social behaviours in NL3(R451C) mice however remain controversial due to inconsistent findings in various assays across different laboratories. Such inconsistencies could plausibly be explained by an increased susceptibility of the NL3(R451C) mouse social phenotype to environmental modulation. To address this, NL3(R451C) mice were housed in standard or enriched housing from 4 weeks of age prior to behavioural testing. Enrichment rearing enhanced direct interactions with the stranger mouse in all mice in the three-chamber social interaction test however, NL3(R451C) mice did not show impairment in social interaction in the three-chamber test, in contrast with previous reports. Environmental enrichment enhanced aggressive behaviour in all mice, and did not specifically alter the heightened aggressive phenotype previously described in NL3(R451C) mice. Specific genotype effects of enrichment included reduced anxiety-like behaviour in WT mice, and lower locomotor activity levels in NL3 mice. While genotype-specific effects of enrichment were not seen on social behaviour, the general increase in affiliative social interaction and aggression seen in all mice, indicates that these behaviours, are vulnerable to change based on housing condition. Mouse models expressing ASD-associated mutations have great utility in elucidating the neurobiology underling development of core traits and it is crucial that efforts are focussed on those models exhibiting robust phenotypes. In light of the findings in the present study, we suggest approaches to improve replicability and reproducibility in mouse models of ASD.
ESTHER : Burrows_2020_Pharmacol.Biochem.Behav_195_172955
PubMedSearch : Burrows_2020_Pharmacol.Biochem.Behav_195_172955
PubMedID: 32474162

Title : Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 - Hosie_2019_Autism.Res_12_1043
Author(s) : Hosie S , Ellis M , Swaminathan M , Ramalhosa F , Seger GO , Balasuriya GK , Gillberg C , Rastam M , Churilov L , McKeown SJ , Yalcinkaya N , Urvil P , Savidge T , Bell CA , Bodin O , Wood J , Franks AE , Bornstein JC , Hill-Yardin EL
Ref : Autism Res , 12 :1043 , 2019
Abstract : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.
ESTHER : Hosie_2019_Autism.Res_12_1043
PubMedSearch : Hosie_2019_Autism.Res_12_1043
PubMedID: 31119867
Gene_locus related to this paper: mouse-3neur , human-NLGN3

Title : Altered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3(R451C) Mouse Model of Autism - Hosie_2018_Front.Cell.Neurosci_12_234
Author(s) : Hosie S , Malone DT , Liu S , Glass M , Adlard PA , Hannan AJ , Hill-Yardin EL
Ref : Front Cell Neurosci , 12 :234 , 2018
Abstract : Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)(R451C) mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3(R451C) mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3(R451C) mice. We report that NL3(R451C) mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3(R451C) mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3(R451C) mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3(R451C) mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.
ESTHER : Hosie_2018_Front.Cell.Neurosci_12_234
PubMedSearch : Hosie_2018_Front.Cell.Neurosci_12_234
PubMedID: 30123111
Gene_locus related to this paper: mouse-3neur

Title : A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice - Burrows_2015_Mol.Autism_6_62
Author(s) : Burrows EL , Laskaris L , Koyama L , Churilov L , Bornstein JC , Hill-Yardin EL , Hannan AJ
Ref : Mol Autism , 6 :62 , 2015
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.
ESTHER : Burrows_2015_Mol.Autism_6_62
PubMedSearch : Burrows_2015_Mol.Autism_6_62
PubMedID: 26583067
Gene_locus related to this paper: mouse-3neur

Title : Reduced susceptibility to induced seizures in the Neuroligin-3(R451C) mouse model of autism - Hill-Yardin_2015_Neurosci.Lett_589_57
Author(s) : Hill-Yardin EL , Argyropoulos A , Hosie S , Rind G , Anderson P , Hannan AJ , O'Brien TJ
Ref : Neuroscience Letters , 589 :57 , 2015
Abstract : Epilepsy is a common comorbidity in patients with autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, Neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3(R451C) compared to WT mice following administration of both 20mg/kg PTZ (1.17+/-0.31 compared to 16.0+/-11.16 events/30min, NL3(R451C) versus WT, respectively) and 30mg/kg PTZ (7.5+/-6.54 compared with 27.8+/-19.9 events/30min, NL3(R451C) versus WT, respectively). NL3(R451C) mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first >3s duration clonic seizure; 14.5min versus 7.25min, 95% CI: 1.625-2.375, p=0.0009, NL3(R451C) versus WT, respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD.
ESTHER : Hill-Yardin_2015_Neurosci.Lett_589_57
PubMedSearch : Hill-Yardin_2015_Neurosci.Lett_589_57
PubMedID: 25592157
Gene_locus related to this paper: mouse-3neur