scholarly journals Changes in Receptive Field Size in Syngap1 +/- Mouse Model of Autism Spectrum Disorder

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Evan Anderson ◽  
Charles A Martin ◽  
Maria Dadarlat
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Receptive Field ◽  
Mouse Model ◽  
Neural Activity ◽  
Autism Spectrum ◽  
Field Size ◽  
Wild Type ◽  
Receptive Field Size ◽  
Field Area

Background and Hypothesis:  Autism spectrum disorder (ASD) is a form of intellectual disability with impairments in social functioning and cognition. Mutations within the SynGAP1 gene are associated with ASD due to over activation of RAS-GTP causing insertion of AMPA receptors onto the post synaptic membrane, and thus early maturation of dendrites. These mutations lead to an excitatory/inhibitory imbalance within the brain, and patients often present with intellectual disability, seizures, and issues of cognition. Research has shown that Syngap1 +/- mice have decreased cortical gray matter brain volume throughout areas involved in the visual system pathway. However, hierarchal visual processing has not been well characterized in a Syngap1 +/- mouse model of autism.   Project Methods:  Using 64 and 128 channel microelectrodes, we recorded the neural activity within V1 of four mice. Neural activity was recorded in response to visual stimuli - testing receptive field size between two wild-type and two Syngap1 +/- mice. Data was run through spike sorting algorithms to identify neurons. Receptive field area for each neuron was then calculated and compared between the two genotypes.   Results:  The receptive field areas of Syngap1 +/- mice were statistically larger (p < 0.01) compared to wild type mice. Syngap1 +/- mice had a mean receptive field area of 450.5 visual degrees (±443.7) and WT mice had a mean receptive field area of 261.1 visual degrees (±187.21). Most of the neurons within Syngap +/- had no distinct receptive field, 67.9%, while only 25.7% of wild type neurons lacked a distinct receptive field.   Conclusion and Potential Impact:  Overall, Syngap1 +/- mice had larger, and less distinct receptive fields compared to wild type mice. Deficiencies in the Syngap1 protein may impair refinement of visual stimuli. Understanding the mechanism of response of missing SynGAP1 can inform directed therapies and interventions to treat patients with the missing gene and manage their intellectual disability.

scholarly journals Larger Receptive Field Size as a Mechanism Underlying Atypical Motion Perception in Autism Spectrum Disorder

2017 ◽  
Vol 5 (5) ◽  
pp. 827-842 ◽  
Author(s):  
Kimberly B. Schauder ◽  
Woon Ju Park ◽  
Duje Tadin ◽  
Loisa Bennetto
Keyword(s):  
Autism Spectrum Disorder ◽  
Receptive Field ◽  
Motion Perception ◽  
Visual Motion ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Field Size ◽  
Contrast Model ◽  
Motion Sensitivity ◽  
Receptive Field Size

Atypical visual motion perception has been widely observed in individuals with autism spectrum disorder (ASD). The pattern of results, however, has been inconsistent. Emerging mechanistic hypotheses seek to explain these variable patterns of atypical motion sensitivity, each uniquely predicting specific patterns of performance across varying stimulus conditions. Here, we investigated the integrity of two such fundamental mechanisms—response gain control and receptive field size. A total of 20 children and adolescents with ASD and 20 typically developing (TD) age- and IQ-matched controls performed a motion discrimination task. To adequately model group differences in both mechanisms of interest, we tested a range of 23 stimulus conditions varying in size and contrast. Results revealed a motion perception impairment in ASD that was specific to the smallest sized stimuli (1°), irrespective of stimulus contrast. Model analyses provided evidence for larger receptive field size in ASD as the mechanism that explains this size-specific reduction of motion sensitivity.

scholarly journals Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

2019 ◽  
Author(s):  
Matthew R. Taylor ◽  
E. Anne Martin ◽  
Brooke Sinnen ◽  
Rajdeep Trilokekar ◽  
Emmanuelle Ranza ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Cellular Interactions ◽  
Loss Of Function ◽  
Wild Type ◽  
Missense Variants

ABSTRACTMissense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss-of-function using knockout mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo. Here, we developed a new gain-of-function assay for Kirrel3 and find that wild-type Kirrel3 induces synapse formation selectively between Kirrel3-expressing cells via homophilic, trans-cellular binding. We tested six disease-associated Kirrel3 missense variants and find that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to wild-type Kirrel3. Two tested variants lack homophilic trans-cellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating Kirrel3 trans-cellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to Kirrel3 function in typical brain development and the consequences of missense variants associated with autism spectrum disorder and intellectual disability.SIGNIFICANCE STATEMENTHere, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 trans-cellular interactions mediate contact recognition and signaling to promote synapse development. Moreover, this is the first study to test the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, provides a framework to understand the etiology of complex neurodevelopmental disorders arising from rare missense variants in synaptic genes.

scholarly journals Effect of Dietary Zinc Supplementation on the Gastrointestinal Microbiota and Host Gene Expression in the Shank3B-/- Mouse Model of Autism Spectrum Disorder

2021 ◽  
Author(s):  
Giselle C Wong ◽  
Yewon Jung ◽  
Kevin Lee ◽  
Chantelle Fourie ◽  
Kim M. Handley ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Autism Spectrum ◽  
Wild Type ◽  
Dietary Zinc ◽  
Knock Out ◽  
Gastrointestinal Problems ◽  
Host Metabolism

Abstract Background: Shank genes are implicated in ~1% of people with autism and mice with Shank3 knock out mutations exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In Shank3B-/- mice, a supplementary zinc diet reverses autism behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiota-brain axis, which may contribute to changes in autism-like behaviours. Methods: Four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out Shank3B-/- mice on either control or supplemented-zinc diets. Bacterial 16S rRNA gene and fungal ITS2 genomic region amplicons were sequenced on the Illumina MiSeq platform and RNA on the Illumina HiSeq platform.Results: Cage, genotype and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8%, 3.9% and 2.3% of the variation, respectively). Fungal diversity differed significantly between wild-type and knock-out Shank3B-/- mice on the control zinc diet, and the fungal biota differed among gut locations. RNA-seq analysis of host (mouse) transcripts revealed differential expression of genes involved in host metabolism that may be regulated by the gut microbiota and genes involved in anti-microbial interactions. Limitations: This study used the Shank3B-/- mouse model of autism spectrum disorder. Heterozygous and homozygous Shank3 gene mutations are found in 1% of the ASD population, only homozygous Shank3 mice were utilised in this study. Any translational conclusions should consider these limitations.Conclusions: By utilising the Shank3B-/- knock-out mouse model we were able to examine the influence of – and interactions between – dietary zinc and ASD-linked host genotype. Differential expression of host antimicrobial interaction genes as well as gut microbiota-regulated host metabolism genes among the treatment groups, suggests that the interplay between gut microbes, the gastrointestinal tract and the brain may play a major role towards the observed amelioration of ASD behaviours seen previously with supplemented dietary zinc. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.

scholarly journals Enhanced negative emotional processing limits behavioral flexibility in a mouse model of autism spectrum disorder

2021 ◽  
Author(s):  
Min Whan Jung ◽  
Eunjoon Kim ◽  
Miru Yun
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Reversal Learning ◽  
Emotional Processing ◽  
Behavioral Flexibility ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Wild Type ◽  
Odor Cues ◽  
Eye Closure

Impaired behavioral flexibility might underlie some of the symptoms associated with autism spectrum disorder (ASD). We investigated whether and how behavioral flexibility is impaired in a mouse model of ASD by testing Shank2-knockout (Shank2-KO) mice in reversal learning. Shank2-KO mice were trained in probabilistic classical conditioning with two odor cues paired with water and air puff. Upon the reversal of cue-outcome contingency, Shank2-KO mice were significantly slower than wild-type mice in reversing their anticipatory licking responses. Shank2-KO mice also showed stronger anticipatory eye closure responses than wild-type mice to the air puff, raising a possibility that the impairment might be because of enhanced negative emotional processing. Indeed, Shank2-KO mice showed intact reversal learning when the strong air puff was replaced with a mild air puff. Shank2-KO mice also showed intact reversal learning between two odor cues predicting rewards with different probabilities. These results indicate that enhanced negative emotional processing suppresses reversal learning despite of intact capability to learn cue-outcome contingency changes in Shank2-KO mice in our behavioral settings. Our findings suggest that behavioral flexibility may be seriously limited by abnormal emotional processing in ASD.

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.

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