scholarly journals Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Musaad A. Alshammari ◽  
Mohammad R. Khan ◽  
Fawaz Alasmari ◽  
Abdulaziz O. Alshehri ◽  
Rizwan Ali ◽  
...  
Keyword(s):  
Mouse Model ◽  
Western Blot ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Wild Type ◽  
Western Blot Assay ◽  
Critical Determinant ◽  
Molecular Features ◽  
Voltage Gated Sodium Channels ◽  
Wild Type Control

The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a condition characterized by deficits in social communication, stereotyped behaviors, and very limited interests. To date, a complete understanding of the molecular components that underlie the AIS in ASD has remained elusive. In this research, we examined the AIS structure in a BTBR T+Itpr3tf/J mouse model (BTBR), a valid model that exhibits behavioral, electrical, and molecular features of autism, and compared this to the C57BL/6J wild-type control mouse. Using Western blot studies and high-resolution confocal microscopy in the prefrontal frontal cortex (PFC), our data indicate disrupted expression of different isoforms of the voltage-gated sodium channels (NaV) at the AIS, whereas other components of AIS such as ankyrin-G and fibroblast growth factor 14 (FGF14) and contactin-associated protein 1 (Caspr) in BTBR were comparable to those in wild-type control mice. A Western blot assay showed that BTBR mice exhibited a marked increase in different sodium channel isoforms in the PFC compared to wild-type mice. Our results provide potential evidence for previously undescribed mechanisms that may play a role in the pathogenesis of autistic-like phenotypes in BTBR mice.

scholarly journals 4225 Evaluation of Neurotransmitters in Channelopathy-Related Epilepsy

2020 ◽  
Vol 4 (s1) ◽  
pp. 95-95
Author(s):  
Sunita N Misra ◽  
Theresa M. Czech ◽  
Jennifer A. Kearney
Keyword(s):  
Mouse Model ◽  
Chart Review ◽  
Retrospective Chart Review ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Wild Type ◽  
Voltage Gated Sodium Channels ◽  
Study Population ◽  
Genotype A

OBJECTIVES/GOALS: Variants in voltage-gated sodium channels (VGSC) are a common cause of severe early onset epilepsy. Changes in CSF neurotransmitters (NT) were identified in 2 cases of VGSC-related epilepsy. Here we investigate NT changes in patients and a novel mouse model of VGSC-related epilepsy. METHODS/STUDY POPULATION: We conducted a single site IRB approved retrospective chart review of patients with VGSC-related epilepsy who underwent CSF NT testing for diagnostic purposes. In parallel, we examined NT levels from the brains of wild-type (WT) and a novel VGSC-related epilepsy mouse model after obtaining IACUC approval. We rapidly isolated forebrain, cortex, striatum, and brainstem from 5-6 animals per sex and genotype. A combination of HPLC with electrochemical detection and mass spectrometry were used to quantify NT levels from brain samples. RESULTS/ANTICIPATED RESULTS: We identified 10 patients with VGSC-related epilepsy who received CSF NT testing. Two of these patients had abnormal NT results including changes to dopamine (DA) or serotonin (5-HT) metabolites. We analyzed NT levels from four brain regions from male and female WT and VGSC-related epilepsy mice. We anticipate that most of the NT levels will be similar to WT, however subtle changes in the DA or 5-HT metabolites may be seen in VGSC-related epilepsy. DISCUSSION/SIGNIFICANCE OF IMPACT: Patients with VGSC-related epilepsy often have autism spectrum disorder, sleep, and movement disorders. Understanding the role of aberrant NT levels in VGSC-related epilepsy may provide additional therapeutic targets that address common neuropsychological comorbidities as well as seizures.

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 Adenosine dysfunction in astrogliosis: cause for seizure generation?

2007 ◽  
Vol 3 (4) ◽  
pp. 353-366 ◽  
Author(s):  
Tianfu Li ◽  
Jing Quan Lan ◽  
Bertil B. Fredholm ◽  
Roger P. Simon ◽  
Detlev Boison
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Therapeutic Intervention ◽  
Neuronal Excitability ◽  
Adenosine Kinase ◽  
Comprehensive Approach ◽  
Mutant Mice ◽  
Wild Type ◽  
Upstream Regulator ◽  
Spontaneous Seizures

AbstractEpilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a crucial link between astrocyte and neuron dysfunction in epilepsy. Here we have studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach that includes a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A1 receptors. In wild-type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosine-removing astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures coincide in a spatio-temporally restricted manner. Importantly, these spontaneous seizures are mimicked by untreated transgenic mice that either overexpress ADK in brain or lack A1 receptors. Conversely, mice with reduced ADK in the forebrain do not develop either astrogliosis or spontaneous seizures. Our studies define ADK as a crucial upstream regulator of A1 receptor-mediated modulation of neuronal excitability, and support the ADK hypothesis of epileptogenesis in which upregulation of ADK during astrogliosis provides a crucial link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

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 Increased axonal bouton stability during learning in the mouse model of MECP2 duplication syndrome

2017 ◽  
Author(s):  
Ryan T. Ash ◽  
Paul G. Fahey ◽  
Jiyoung Park ◽  
Huda Y. Zoghbi ◽  
Stelios M. Smirnakis
Keyword(s):  
Motor Learning ◽  
Mouse Model ◽  
Dendritic Spine ◽  
Pyramidal Neuron ◽  
Structural Plasticity ◽  
Autism Spectrum ◽  
Wild Type ◽  
Syndromic Autism ◽  
Mecp2 Duplication Syndrome ◽  
Duplication Syndrome

ABSTRACTMECP2-duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding Methyl-CpG-binding protein 2. Mice overexpressing MECP2 demonstrate altered patterns of learning and memory, including enhanced motor learning. Previous work associated this enhanced motor learning to abnormally increased stability of dendritic spine clusters formed in the apical tuft of corticospinal, area M1, neurons during rotarod training. In the current study, we measure the structural plasticity of axonal boutons in Layer 5 (L5) pyramidal neuron projections to layer 1 of area M1 during motor learning. In wild-type mice we find that during rotarod training, bouton formation rate changes minimally, if at all, while bouton elimination rate doubles. Notably, the observed upregulation in bouton elimination with learning is absent in MECP2-duplication mice. This result provides further evidence of imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination doubles with motor learning in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor learning.SIGNIFICANCE STATEMENTAbnormal balance between synaptic stability and plasticity is a feature of several autism spectrum disorders, often corroborated by in vivo studies of dendritic spine turnover. Here we provide the first evidence that abnormally increased stability of axonal boutons, the presynaptic component of excitatory synapses, occurs during motor learning in the MECP2 duplication syndrome mouse model of autism. In contrast, in normal controls, axonal bouton elimination in L5 pyramidal neuron projections to layer 1 of area M1 doubles with motor learning. The fact that axonal projection boutons get eliminated, while corticospinal dendritic spines get consolidated with motor learning in layer 1 of area M1, suggests that structural plasticity manifestations differ across different M1 microcircuits.

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):  
Mouse Model ◽  
Gut Microbiome ◽  
Autism Spectrum ◽  
Wild Type ◽  
Dietary Zinc ◽  
Host Genotype ◽  
Knock Out ◽  
Treatment Groups ◽  
Gastrointestinal Problems ◽  
Host Metabolism

AbstractShank 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-microbiome-brain axis, which may contribute to changes in autism-like behaviours. To test this, 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. 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. 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. 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.ImportancePreviously, supplemental dietary zinc in the Shank3B−/− mouse model of autism spectrum disorder resulted in observations of ASD behaviours reversal; in this study we also used the Shank3B−/− mouse model to examine the influence of – and interaction between – dietary zinc and ASD-linked host genotype. Sample location along the gastrointestinal tract, genotype and zinc diet explained some of the variation in the microbiota data, with notable bacterial differences between treatment groups. Differential expression of host genes between treatment groups, including antimicrobial interaction genes and gut microbiota-regulated host metabolism genes, 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 results widen the scope towards manipulating both dietary zinc and the microbiota itself to ameliorate ASD-related behaviours and associated gastrointestinal issues.

scholarly journals Hyperactive ACC-MDT Pathway Suppresses Prepulse Inhibition in Mice

2020 ◽  
Author(s):  
Yangsik Kim ◽  
Young Woo Noh ◽  
Kyungdeok Kim ◽  
Eunjoon Kim
Keyword(s):  
Prepulse Inhibition ◽  
Synaptic Input ◽  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Anterior Cingulate ◽  
Wild Type ◽  
Hyperactivity Disorder ◽  
Excitatory Synaptic Input ◽  
Spectrum Disorders

Abstract Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice.

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.

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.

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