GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation

Jiang, Dongyun; Wu, Zheng; Forsyth, Cody; Hu, Yi; Yee, Siu Pok; Chen, Gong

doi:10.1186/s13041-018-0375-6

Cited by 24 publications

(12 citation statements)

References 66 publications

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“…However, no shift was observed in the Nlgn2 knockout mice, a model of anxiety [21,63]. These mice showed decreased avoidance of the conditioned tone, a finding consistent with recent observations of learning impairments in mice that have an equivalent knockout of the Nlgn2 protein [64,65]. However, and independent of possible learning impairments, mice lacking Nlg2 are highly anxious, indicating that overgeneralization does not always accompany increased anxiety.…”

Section: Discussionsupporting

confidence: 80%

Wide sensory filters underlie performance in memory-based discrimination and generalization

2019

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The way animals respond to a stimulus depends largely on an internal comparison between the current sensation and the memory of previous stimuli and outcomes. We know little about the accuracy with which the physical properties of the stimuli influence this type of memory-based discriminative decisions. Research has focused largely on discriminations between stimuli presented in quick succession, where animals can make relative inferences (same or different; higher or lower) from trial to trial. In the current study we used a memory-based task to explore how the stimulus’ physical properties, in this case tone frequency, affect auditory discrimination and generalization in mice. Mice performed ad libitum while living in groups in their home quarters. We found that the frequency distance between safe and conditioned sounds had a constraining effect on discrimination. As the safe-to-conditioned distance decreased across groups, performance deteriorated rapidly, even for frequency differences significantly larger than reported discrimination thresholds. Generalization width was influenced both by the physical distance and the previous experience of the mice, and was not accompanied by a decrease in sensory acuity. In conclusion, memory-based discriminations along a single stimulus dimension are inherently hard, reflecting a high overlap between the memory traces of the relevant stimuli. Memory-based discriminations rely therefore on wide sensory filters.

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Section: Discussionsupporting

confidence: 80%

Wide sensory filters underlie performance in memory-based discrimination and generalization

2019

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“…Reduced NLGN2 expression in the prefrontal cortex (PFC) is involved in attention deficits induced by peripubertal stress which can be reversed by virus-mediated NLGN2 rescue (Tzanoulinou et al, 2016). Animal models using the genetic engineering method showed that Nlgn 2 R215H knock-in (KI) mouse exhibited schizophrenia-like behaviors and higher anxiety behaviors with significant reduction of mIPSCs in the dentate gyrus (DG), reduced subunit GABA-A γ2 expression levels, and reduced presynaptic PV and VGAT levels, while there were no changes of miniature excitatory postsynaptic currents (mEPSCs), vesicular glutamate transporter (VGLUT), and postsynaptic density protein 95 (PSD95) expression levels (Jiang et al, 2018;Van Zandt et al, 2019). NLGN2 of ACC is involved in KCC2-mediated abnormal GABAergic transmission induced aggressive behaviors (Jager et al, 2020).…”

Section: Nlgn2 3 Andmentioning

confidence: 99%

GABAergic System Dysfunction in Autism Spectrum Disorders

Zhao

Mao

Zhu

et al. 2022

Front. Cell Dev. Biol.

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Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.

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“…Previous studies have reported that rodent models with autism-associated genetic mutations can display an exaggerated startle response, or impaired pre-pulse inhibition, to an acoustic stimulus (38–41). These impairments are associated with deficits in sensory gating and auditory processing often reported in ASD patients (42,43).…”

Section: Resultsmentioning

confidence: 99%

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Martin-Kenny

Bérubé

2020

Preprint

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24Background: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism 25 susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X 26 intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) 27 patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours 28 are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in 29 excitatory neurons of the forebrain and performed a battery of behavioural assays that assess 30 autistic-like behaviours. 31Methods: Male and female mice with a postnatal conditional knockout of Atrx were tested in a 32 battery of behavioural tests that assess autistic features. We utilized paradigms that measure social 33 behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were 34 calculated by two-way repeated measures ANOVA with Sidak's multiple comparison test or 35 unpaired Student's T-tests as indicated. 36Results: The behaviour tests revealed no significant differences between Atrx-cKO and control 37 mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, 38 these changes did not correlate with social deficits. We additionally observed sex-specific 39 differences in sociability, vertical episodes, and acoustic startle response when results were 40 analyzed by sex. 41 Conclusion: The postnatal knockout of Atrx in forebrain excitatory neurons does not lead to 42 autism-related behaviours in male or female mice.43 44 Keywords: autism spectrum disorder, ATRX, sex differences, social behaviours, repetitive 45 behaviours, startle response, genetically engineered mice, Cre/loxP system 46 Background 47 Autism spectrum disorder (ASD) is a behaviourally defined condition characterized by 48 deficits in social and communicative abilities, impaired sensory gating, as well as the presence of 49 stereotyped behaviours (1,2). Recent work has highlighted the important contribution of de novo 50 variants and inherited copy number variants in ASD, confirming a strong genetic component of 51 this disease (1-3). Numerous autism susceptibility genes have been identified and shown to share 52 commonalities in synaptic, transcriptional, and epigenetic mechanisms (4-6). Mouse models have 53typically been used to investigate the behavioural implications of genetic mutations associated 54 with ASD (7,8). However, these studies often omit the investigation of the sex-specific effects of 55 these genetic mutations, limiting the potential translational applications. In the general population, 56 ASD occurs at a 4:1 male:female ratio, highlighting the need to study the outcome of genetic 57 mutations in both male and female model systems (1,2). 58In this study, we describe the impact of targeted inactivation of Atrx in glutamatergic 59 neurons on behaviours related to autism in male and female mice. ATRX belongs to the SWI/SNF 60 family of chromatin remodeling factors (9,10). Mutations in ...

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GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation

Cited by 24 publications

References 66 publications

Wide sensory filters underlie performance in memory-based discrimination and generalization

Wide sensory filters underlie performance in memory-based discrimination and generalization

GABAergic System Dysfunction in Autism Spectrum Disorders

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

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