Hannan AJ

References (8)

Title : Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task - Li_2024_Psychopharmacology.(Berl)__
Author(s) : Li S , May C , Pang TY , Churilov L , Hannan AJ , Johnson KA , Burrows EL
Ref : Psychopharmacology (Berl) , : , 2024
Abstract : RATIONALE: Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. OBJECTIVE: The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. METHODS: NL3(R451C) and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. RESULTS: In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3(R451C) and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3(R451C) mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3(R451C) mice. CONCLUSIONS: NL3(R451C) mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3(R451C) mutation by suggesting that this mutation may lead to selective alterations in attentional processes.
ESTHER : Li_2024_Psychopharmacology.(Berl)__
PubMedSearch : Li_2024_Psychopharmacology.(Berl)__
PubMedID: 38170320
Gene_locus related to this paper: human-NLGN3 , mouse-3neur

Title : Mice with an autism-associated R451C mutation in neuroligin-3 show a cautious but accurate response style in touchscreen attention tasks - Burrows_2021_Genes.Brain.Behav__e12757
Author(s) : Burrows EL , May C , Hill T , Churliov L , Johnson KA , Hannan AJ
Ref : Genes Brain Behav , :e12757 , 2021
Abstract : One of the earliest identifiable features of Autism Spectrum Disorder (ASD) is altered attention. Mice expressing the ASD-associated R451C mutation in synaptic adhesion protein neuroligin-3 (NL3) exhibit impaired reciprocal social interactions and repetitive and restrictive behaviors. The role of this mutation in attentional abnormalities has not been established. We assessed attention in male NL3(R451C) mice using two well-established tasks in touchscreen chambers. In the 5-choice serial reaction task (5CSRT), rodents were trained to attend to light stimuli that appear in any one of 5 locations. While no differences between NL3(R451C) and WT mice were seen in accuracy or omissions, slower response times and quicker reward collection latencies were seen across all training and probe trials. In the rodent continuous-performance test (rCPT), animals were required to discriminate, and identify a visual target pattern over multiple distractor stimuli. NL3(R451C) mice displayed enhanced ability to attend to stimuli when task-load was low during training and baseline but lost this advantage when difficulty was increased by altering task parameters in probe trials. NL3(R451C) mice made less responses to the distractor stimuli, exhibiting lower false alarm rates during all training stages and in probe trials. Slower response times and quicker reward latencies were consistently seen in NL3(R451C) mice in the rCPT. Slower response times are a major cognitive phenotype reported in ASD patients and are indicative of slower processing speed. Enhanced attention has been shown in a subset of ASD patients and we have demonstrated this phenotype also exists in the NL3(R451C) mouse model.
ESTHER : Burrows_2021_Genes.Brain.Behav__e12757
PubMedSearch : Burrows_2021_Genes.Brain.Behav__e12757
PubMedID: 34085373
Gene_locus related to this paper: human-NLGN3

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 : Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference - Norris_2019_Mol.Autism_10_42
Author(s) : Norris RHC , Churilov L , Hannan AJ , Nithianantharajah J
Ref : Mol Autism , 10 :42 , 2019
Abstract : Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3 (-/y) and Nlgn3 (R451C)). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms.
ESTHER : Norris_2019_Mol.Autism_10_42
PubMedSearch : Norris_2019_Mol.Autism_10_42
PubMedID: 31827744
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 : Social Isolation Alters Social and Mating Behavior in the R451C Neuroligin Mouse Model of Autism - Burrows_2017_Neural.Plast_2017_8361290
Author(s) : Burrows EL , Eastwood AF , May C , Kolbe SC , Hill T , McLachlan NM , Churilov L , Hannan AJ
Ref : Neural Plast , 2017 :8361290 , 2017
Abstract : Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by impaired social communication and restrictive and repetitive behaviors. Mice serve as an ideal candidate organism for studying the neural mechanisms that subserve these symptoms. The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice. Social interactions with female mice have not been characterized and in the present study were assessed in male NL3R451C and WT mice. Mice were housed in social and isolation conditions to test for isolation-induced increases in social interaction. Tests were repeated to investigate potential differences in interaction in naive and experienced mice. We identified heightened interest in mating and atypical aggressive behavior in NL3R451C mice. NL3R451C mice exhibited normal social interaction with WT females, indicating that abnormal aggressive behavior towards females is not due to altered motivation to engage. Social isolation rearing heightened interest in social behavior in all mice. Isolation housing selectively modulated the response to female pheromones in NL3R451C mice. This study is the first to show altered mating behavior in the NL3R451C mouse and has provided new insights into the aggressive phenotype in this model.
ESTHER : Burrows_2017_Neural.Plast_2017_8361290
PubMedSearch : Burrows_2017_Neural.Plast_2017_8361290
PubMedID: 28255463
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