scholarly journals Diminished cortical excitation and elevated inhibition during perceptual impairments in a mouse model of autism

2019 ◽  
Author(s):  
Joseph Del Rosario ◽  
Anderson Speed ◽  
Hayley Arrowood ◽  
Cara Motz ◽  
Machelle Pardue ◽  
...  
Keyword(s):  
Visual Perception ◽  
Mouse Model ◽  
Inhibitory Activity ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Neuron Activity ◽  
Conflicting Evidence ◽  
Inhibitory Population ◽  
Sensory Activity ◽  
Speed Accuracy

AbstractSensory impairments are a core feature of autism spectrum disorder (ASD). These impairments affect visual perception (Robertson and Baron-Cohen, 2017), and have been hypothesized to arise from imbalances in cortical excitatory and inhibitory activity (Rubenstein and Merzenich, 2003; Nelson and Valakh, 2015; Sohal and Rubenstein, 2019); however, there is little direct evidence testing this hypothesis in identified excitatory and inhibitory neurons during impairments of sensory perception. Several recent studies have examined cortical activity in transgenic mouse models of ASD (Goel et al., 2018; Antoine et al., 2019; Lazaro et al., 2019), but have provided conflicting evidence for excitatory versus inhibitory activity deficits. Here, we utilized a genetically relevant mouse model of ASD (CNTNAP2−/− knockout, KO; Arking et al., 2008; Penagarikano et al., 2011) and directly recorded putative excitatory and inhibitory population spiking in primary visual cortex (V1) while measuring visual perceptual behavior (Speed et al., 2019). We found quantitative impairments in the speed, accuracy, and contrast sensitivity of visual perception in KO mice. These impairments were simultaneously associated with elevated inhibitory and diminished excitatory neuron activity evoked by visual stimuli during behavior, along with aberrant 3 – 10 Hz oscillations in superficial cortical layers 2/3 (L2/3). These results establish that perceptual deficits relevant for ASD can arise from diminished sensory activity of excitatory neurons in feedforward layers of cortical circuits.

scholarly journals Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome

2018 ◽  
Vol 115 (42) ◽  
pp. 10744-10749 ◽  
Author(s):  
Wei-Hsiang Huang ◽  
David C. Wang ◽  
William E. Allen ◽  
Matthew Klope ◽  
Hailan Hu ◽  
...  
Keyword(s):  
Social Interaction ◽  
Mouse Model ◽  
Behavioral Problems ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Critical Window ◽  
Genetic Mouse Model ◽  
Expression Of Genes ◽  
Syndromic Autism ◽  
Level 3

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

scholarly journals Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

2021 ◽  
Author(s):  
Chaojuan Yang ◽  
Yonglu Tian ◽  
Feng Su ◽  
Yangzhen Wang ◽  
Mengna Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Visual Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Local Network ◽  
V1 Neurons ◽  
Processing Deficits

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

Behavioural and EEG atypicalities during rest, visual perception, and cognitive control in autistic adults

2020 ◽  
Author(s):  
Amandine Lassalle ◽  
Michael X Cohen ◽  
Laura Dekkers ◽  
Elizabeth Milne ◽  
Rasa Gulbinaite ◽  
...  
Keyword(s):  
Visual Perception ◽  
Cognitive Control ◽  
Visual Processing ◽  
Autism Spectrum ◽  
Neural Dynamics ◽  
Simple Explanation ◽  
Control Task ◽  
Neural Structure ◽  
Eeg Power ◽  
Autistic Adults

Background: People with an Autism Spectrum Condition diagnosis (ASD) are hypothesized to show atypical neural dynamics, reflecting differences in neural structure and function. However, previous results regarding neural dynamics in autistic individuals have not converged on a single pattern of differences. It is possible that the differences are cognitive-set-specific, and we therefore measured EEG in autistic individuals and matched controls during three different cognitive states: resting, visual perception, and cognitive control.Methods: Young adults with and without an ASD (N=17 in each group) matched on age (range 20 to 30 years), sex, and estimated Intelligence Quotient (IQ) were recruited. We measured their behavior and their EEG during rest, a task requiring low-level visual perception of gratings of varying spatial frequency, and the “Simon task” to elicit activity in the executive control network. We computed EEG power and Inter-Site Phase Clustering (ISPC; a measure of connectivity) in various frequency bands.Results: During rest, there were no ASD vs. controls differences in EEG power, suggesting typical oscillation power at baseline. During visual processing, without pre-baseline normalization, we found decreased broadband EEG power in ASD vs. controls, but this was not the case during the cognitive control task. Furthermore, the behavioral results of the cognitive control task suggest that autistic adults were better able to ignore irrelevant stimuli.Conclusions: Together, our results defy a simple explanation of overall differences between ASD and controls, and instead suggest a more nuanced pattern of altered neural dynamics that depend on which neural networks are engaged.

Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

2019 ◽  
Author(s):  
German I. Todorov ◽  
Karthikeyan Mayilvahanan ◽  
David Ashurov ◽  
Catarina Cunha
Keyword(s):  
Mouse Model ◽  
Autism Spectrum ◽  
Obsessive Compulsive ◽  
Cancer Treatments ◽  
Knock Out ◽  
Treatment Priority ◽  
Underlying Mechanisms ◽  
Knock Out Mice ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Lichtman ◽  
Eyal Bergmann ◽  
Alexandra Kavushansky ◽  
Nadav Cohen ◽  
Nina S. Levy ◽  
...  
Keyword(s):  
Social Behavior ◽  
Functional Connectivity ◽  
Mouse Model ◽  
Ampa Receptor ◽  
Social Preference ◽  
Autism Spectrum ◽  
Receptor Trafficking ◽  
Anterior Cingulate ◽  
The Impact ◽  
Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Chang-geng Song ◽  
Xin Kang ◽  
Fang Yang ◽  
Wan-qing Du ◽  
Jia-jia Zhang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
Interneuron Development

Abstract In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

Comparison of cognitive functions children with the autism spectrum disorders and schizophrenia

2017 ◽  
Vol 41 (S1) ◽  
pp. S457-S458
Author(s):  
N. Zvereva ◽  
N. Simashkova ◽  
A. Koval-Zaitsev
Keyword(s):  
Autism Spectrum Disorder ◽  
Visual Perception ◽  
Cognitive Functioning ◽  
Cognitive Functions ◽  
Early Onset ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Early Onset Schizophrenia ◽  
Competing Interest ◽  
Autistic Disorders

IntroductionAutism spectrum disorder and early onset schizophrenia have many similar symptoms, however, these are different disorders. It is important to identify the main similarities\differences in the structure of cognitive impairment to define further assistance these children correctly. We distinguished two options for cognitive defect (total and partial) in children with schizophrenia.AimsComparison of cognitive functions at children with autism spectrum disorder and early onset schizophrenia.ObjectivesTwo groups with autism spectrum disorder (ASD1 – 22 patients of MHRC mean age 8.9; ASD2 – 27 pupils of special school mean age 7,4). Two groups with early onset schizophrenia (F20.8 – 16 patients of MHRC mean age 10,2; F21 – 18 patients of MHRC mean age 10.0).MethodsBattery of pathopsychological tests for assessing cognitive functions (memory, attention, thinking), test figures of Leeper for visual perception. Z-scales were used for estimation of cognitive deficit or defect.ResultsPatients demonstrate variety of cognitive functioning. Normal cognitive functioning: ASD1* – 22%, F20.8 – 18%, F21* – 50% (* – P ≤ 0.05); partial cognitive defect: ASD1 – 27%, F20.8 – 18%, F21 – 22%; total cognitive defect: ASD1** – 50%, F20.8 – 64%, F21** – 27% (** – P ≤ 0.01). ASD1 and F20 were the worth in thinking. Children ASD1 and ASD2 demonstrate similar success in recognizing Leeper's figures.ConclusionsThere are some common features of cognitive development in children with severe forms of ASD and early onset schizophrenia, first of all in thinking.No significant differences obtained between severe – mild forms of autistic disorders in visual perception (ASD1 and ASD2).Disclosure of interestThe authors have not supplied their declaration of competing interest.

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