Neurobiology of Autism and Intellectual Disability

Full Range ◽

Therapeutic Targets ◽

Autism Spectrum ◽

Fmr1 Gene ◽

Health Concern ◽

Complex Disorders ◽

Mglur5 Antagonist ◽

Fragile X syndrome (FXS) is a neurodevelopmental disorder that manifests with a range of cognitive, behavioral, and social impairments. It is a monogenetic disease caused by silencing of the FMR1 gene, in contrast to autism spectrum disorder (ASD) that is a behaviorally-defined set of complex disorders. Because ASD is a major and growing public health concern, current research is focused on identifying common therapeutic targets among patients with different molecular etiologies. Due to the prevalence of ASD in FXS and its shared neurophysiology with ASD, FXS has been extensively studied as a model for ASD. Studies in the animal models have provided breakthrough insights into the pathophysiology of FXS that have led to novel therapeutic targets for its core deficits (e.g., mGluR theory of fragile X). Yet recent clinical trials of both GABA-B agonist and mGluR5 antagonist revealed a lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS. Recent research shows promise for the mapping of the multitude of genetic variants in ASD onto shared pathways with FXS. Nonetheless, in light of the huge level of locus heterogeneity in ASD, further effort in finding convergence in specific molecular pathways and reliable biomarkers is required in order to perform targeted treatment trials with sufficient sample size. This chapter focuses on the neurobehavioral phenotype caused by a full-mutation of the FMR1 gene, namely FXS, and the neurobiology of this disorder of relevance to the targeted molecular treatments of its core symptoms.

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

Clinical & Investigative Medicine ◽

10.25011/cim.v30i4.2850 ◽

2007 ◽

Vol 30 (4) ◽

pp. 80

Author(s):

B Eadie ◽

B Christie

Keyword(s):

Mouse Model ◽

Learning And Memory ◽

Fragile X Syndrome ◽

Knockout Mice ◽

Fragile X ◽

Single Gene ◽

Autism Spectrum ◽

Fmr1 Gene ◽

Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

Fragile X syndrome: Lessons learned from the most translated neurodevelopmental disorder in clinical trials

Translational Neuroscience ◽

10.1515/tnsci-2017-0002 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 8

Author(s):

Phan Q. Duy ◽

Dejan B. Budimirovic

Keyword(s):

Clinical Trials ◽

Fragile X Syndrome ◽

Fragile X ◽

Full Range ◽

Autism Spectrum ◽

Lessons Learned ◽

Success Story ◽

Negative Results ◽

Neural Signaling

AbstractFragile X syndrome (FXS) is the leading genetic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID) worldwide. Preclinical successes in understanding the biology of FXS have led to numerous translational attempts in human clinical trials of therapeutics that target the excitatory/inhibitory neural signaling imbalances thought to underlie FXS. Despite the preclinical success story, the negative results of the human clinical trials have been deemed to be at least in part disappointing by the field. In this commentary, we contend that such negative studies results in clinical trials may actually propel the FXS field forward by serving as important lessons for designing and implementing improved future clinical trials such that can objectively assess the full range of responses to new therapeutics.

CHD8 regulates gut epithelial cell function and affects autism-related behaviours through the gut-brain axis

10.1101/2021.10.02.462735 ◽

2021 ◽

Author(s):

Ipsita Chaterjee ◽

Dmitriy Getselter ◽

Nasreen Ghaneem ◽

Shai Bel ◽

Evan Elliott

Keyword(s):

Epithelial Cells ◽

Cell Function ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Direct Role ◽

Tuft Cells ◽

Core Symptoms ◽

The Relationship ◽

Specific Deletion

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.

Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders.

Current Medicinal Chemistry ◽

10.2174/0929867328666211125091811 ◽

2021 ◽

Vol 28 ◽

Author(s):

Daljeet Singh Dhanjal ◽

Sonali Bhardwaj ◽

Chirag Chopra ◽

Reena Singh ◽

Jiri Patocka ◽

...

Keyword(s):

Conventional Medicine ◽

Treatment Options ◽

Autism Spectrum ◽

Autistic Children ◽

Children With Asd ◽

Drastic Increase ◽

Spectrum Disorders ◽

Approved Drugs ◽

: Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high-income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families and parents of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently, N,N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, CAM approach and efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

Hyperexcitability and loss of feedforward inhibition in the Fmr1KO lateral amygdala

10.1101/2020.04.21.053652 ◽

2020 ◽

Author(s):

E. Mae Guthman ◽

Matthew N. Svalina ◽

Christian A. Cea-Del Rio ◽

J. Keenan Kushner ◽

Serapio M. Baca ◽

...

Keyword(s):

Anxiety Disorders ◽

Fragile X ◽

Autism Spectrum ◽

Synaptic Function ◽

Excitatory Synapses ◽

Lateral Amygdala ◽

Early Postnatal Development ◽

Whole Cell Patch Clamp ◽

Patch Clamp Electrophysiology

SummaryFragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorders (ASDs), and anxiety disorders. The disruption in the function of the FMR1 gene results in a range of alterations in cellular and synaptic function. Previous studies have identified dynamic alterations in inhibitory neurotransmission in early postnatal development in the amygdala of the mouse model of FXS. Yet little is known how these changes alter microcircuit development and plasticity in the lateral amygdala (LA). Using whole-cell patch clamp electrophysiology, we demonstrate that principal neurons (PNs) in the LA exhibit hyperexcitability with a concomitant increase in the synaptic strength of excitatory synapses in the BLA. Further, reduced feed-forward inhibition appears to enhance synaptic plasticity in the FXS amygdala. These results demonstrate that plasticity is enhanced in the amygdala of the juvenile Fmr1 KO mouse and that E/I imbalance may underpin anxiety disorders commonly seen in FXS and ASDs.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Journal of Cannabis Research ◽

10.1186/s42238-021-00108-7 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Serap Bilge ◽

Barış Ekici

Keyword(s):

Autism Spectrum Disorder ◽

Social Interaction ◽

Behavioral Problems ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Average Dose ◽

The Core ◽

Abstract Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Microbiome-Specific Statistical Modeling Identifies Interplay Between Gastrointestinal Microbiome and Neurobehavioral Outcomes in Patients With Autism: A Case Control Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.682454 ◽

2021 ◽

Vol 12 ◽

Author(s):

Minshi Huang ◽

Jun Liu ◽

Kevin Liu ◽

Jierong Chen ◽

Zhen Wei ◽

...

Keyword(s):

Dietary Habits ◽

Gastrointestinal Symptoms ◽

Autism Spectrum ◽

Case Control ◽

Living Environment ◽

Degree Relative ◽

Gastrointestinal Microbiome ◽

Core Symptoms ◽

Tyrosine Biosynthesis

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear mechanisms of pathogenesis. Gastrointestinal microbiome alterations were found to correlate with ASD core symptoms, but its specific role in ASD pathogenesis has not been determined. In this study, we used a case-control strategy that simultaneously compared the ASD gastrointestinal microbiome with that from age-sex matched controls and first-degree relative controls, using a statistical framework accounting for confounders such as age. Enterobacteriaceae (including Escherichia/Shigella) and Phyllobacterium were significantly enriched in the ASD group, with their relative abundances all following a pattern of ASD > first degree relative control > healthy control, consistent with our hypothesis of living environment and shared microbial and immunological exposures as key drivers of ASD gastrointestinal microbiome dysbiosis. Using multivariable omnibus testing, we identified clinical factors including ADOS scores, dietary habits, and gastrointestinal symptoms that covary with overall microbiome structure within the ASD cohort. A microbiome-specific multivariate modeling approach (MaAsLin2) demonstrated microbial taxa, such as Lachnoclostridium and Tyzzerella, are significantly associated with ASD core symptoms measured by ADOS. Finally, we identified alterations in predicted biological functions, including tryptophan and tyrosine biosynthesis/metabolism potentially relevant to the pathophysiology of the gut-brain-axis. Overall, our results identified gastrointestinal microbiome signature changes in patients with ASD, highlighted associations between gastrointestinal microbiome and clinical characteristics related to the gut-brain axis and identified contributors to the heterogeneity of gastrointestinal microbiome within the ASD population.

Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder

BioMed Research International ◽

10.1155/2021/4359308 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Areerat Hnoonual ◽

Charunee Jankittunpaiboon ◽

Pornprot Limprasert

Keyword(s):

Autism Spectrum Disorder ◽

Fragile X ◽

Single Gene ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Fmr1 Gene ◽

Normal Male ◽

Cgg Repeat ◽

Cgg Repeats ◽

Normal Controls

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

10.1101/338988 ◽

2018 ◽

Cited By ~ 1

Author(s):

Carla E. M. Golden ◽

Michael S. Breen ◽

Lacin Koro ◽

Sankalp Sonar ◽

Kristi Niblo ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Rna Binding ◽

Fragile X ◽

Point Mutations ◽

Autism Spectrum ◽

Attention Deficits ◽

Hub Genes ◽

Transcriptional Profiles

AbstractFragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.Significance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.