Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment

Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.

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Hemispheric Coherence in ASD with and without Comorbid ADHD and Anxiety

BioMed Research International ◽

10.1155/2016/4267842 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

A. Saunders ◽

I. J. Kirk ◽

K. E. Waldie

Keyword(s):

Developmental Disorders ◽

Primary Motor Cortex ◽

Brain Connectivity ◽

Occipital Lobe ◽

Autism Spectrum ◽

Adhd Group ◽

Comorbid Conditions ◽

Resting State Functional Connectivity ◽

Comorbid Adhd ◽

The Brain

There is a growing body of evidence suggesting that altered brain connectivity may be a defining feature of disorders such as autism spectrum disorder (ASD), anxiety, and ADHD. This study investigated whether resting state functional connectivity, measured by 128-channel EEG oscillation coherence, differs between developmental disorders. Analyses were conducted separately on groups with and without comorbid conditions. Analyses revealed increased coherence across central electrodes over the primary motor cortex and decreased coherence in the frontal lobe networks in those with ASD compared to neurotypical controls. There was increased coherence in occipital lobe networks in the ADHD group compared to other groups. Symptoms of generalised anxiety were positively correlated with both frontal-occipital intrahemispheric (alpha only) coherence and occipital interhemispheric coherence (alpha, approaching theta band). The patterns of coherence in the ASD pure group were different when comorbid conditions were included in the analyses, suggesting that aberrant coherence in the frontal and central areas of the brain is specifically associated with ASD. Our findings support the idea that comorbid conditions are additive, rather than being symptoms of the same disorder.

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Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer

Blood ◽

10.1182/blood-2019-121033 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. SCI-48-SCI-48

Author(s):

Cigall Kadoch

Keyword(s):

Chromatin Remodeling ◽

Developmental Disorders ◽

Human Cancer ◽

Malignant Rhabdoid Tumor ◽

Advisory Committees ◽

Sequencing Studies ◽

Genes Encoding ◽

Therapeutic Development ◽

Chromatin Remodeling Complexes ◽

And Function

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Struktur Otak dan Keberfungsiannya pada Anak dengan Gangguan Spektrum Autis: Kajian Neuropsikologi

Buletin Psikologi ◽

10.22146/buletinpsikologi.25163 ◽

2017 ◽

Vol 25 (1) ◽

Author(s):

Nurussakinah - Daulay

Keyword(s):

Autism Spectrum Disorders ◽

Developmental Disorders ◽

Sensory Information ◽

Children With Autism ◽

Autism Spectrum ◽

Sensory Stimuli ◽

Spectrum Disorders ◽

The Brain ◽

Sensory Process

The purpose of this article is to understand the basic neuroanatomy of the brain and the neurodevelopmental characteristics of children with autism spectrum disorders. Children with autism spectrum disorders are children with complex developmental disorders, based on a neuropsychological approach, a disorder experienced by a child with autism due to abnormalities in the structure and biochemistry of the brain, as well as the interference in integrating sensory information received by the environment. Disturbances in the sensory process include how to obtain sensory information (sensory procesing), how to process the information (sensory procesing), and how to move the muscles and perform a series of movements in response to sensory stimuli received.

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Functional Connectivity: Application to Developmental Disorders

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0075 ◽

2013 ◽

pp. 995-1009

Author(s):

Luke Bloy ◽

Ragini Verma ◽

Timothy P.L. Roberts

Keyword(s):

Functional Connectivity ◽

Developmental Disorders ◽

Brain Activity ◽

Structural Connectivity ◽

Autism Spectrum ◽

Great Success ◽

Experimental Conditions ◽

Neuronal Ensembles ◽

The Brain

Noninvasive imaging and electrophysiological methods have been developed to facilitate the in vivo investigation of brain function and dysfunction. Such methods have been employed, with great success, to the functional mapping of the brain, as well as the characterization of the temporal activity of these regions during a variety of tasks and experimental conditions. These methods are however inadequate to fully capture our current understanding of brain activity, as the complex interplay of structurally and functionally connected networks of neuronal ensembles. Here we offer an overview of the methodological advancements that have been made to better facilitate the investigation of connectivity in the brain and its relationship to development and pathology. We have focused primarily on in vivo modalities that have been most widely adopted, namely fMRI and electro/magneto encephalography for the investigation of functional connectivity and diffusion MRI for structural connectivity. Finally, the application of these methodologies to the study of neurodevelopmental disorders, such as the autism spectrum disorders, schizophrenia and attention deficit hyperactivity disorder, is presented.

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Critical review on role of Microbiota transfer therapy in Autism spectrum disorder

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i3.4820 ◽

2021 ◽

Vol 12 (3) ◽

pp. 2095-2114

Author(s):

Hemalakshmi R ◽

Pavithra Amritkumar

Keyword(s):

Autism Spectrum Disorder ◽

Gut Microbiota ◽

Developmental Disorders ◽

Treatment Options ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Intestinal Microbiome ◽

The Brain

Autism spectrum disorder (ASD) is a developmental disorder that affects behaviour and communication. It can be diagnosed at any age, although the symptoms generally appear in the first two years of life. Autism is also known as a "spectrum" disorder because there is wide variation in the severity and type of patient experience. Intestinal dysbiosis remains a risk factor for several neuron-developmental disorders and physiological diseases such as ASD. The gut microbiome in human influence the total metabolomic profile and thus has an impact on the overall health of human. The brain-intestinal axis concept demonstrates the interaction between the brain and the diverse gut microbial population. Recent findings show that ASD symptoms in affected individuals are linked with the altered intestinal microbiome. The current treatment modality for the symptoms of ASD are limited to Applied Behaviour Analysis (ABA) and FDA approved medications like Risperidone and Aripiprazole. Individuals with ASD appear to be susceptible to adverse effects of these medications. Current accumulating studies indicate that Microbiota Transfer Therapy (MTT) is a promising technique for treating ASD. MTT involves in vitro batch culture of gut microbiota, which is viewed as a quick and accessible method. It has provided encouraging results by improving ASD-related gastrointestinal (GI) and behavioural symptoms in affected individuals. The present review focuses on the link between gut dysbiosis and ASD, analyses the available clinical studies related to various treatment options and describes the role of MTT as a promising therapy of bringing back the healthy gut microbiota composition in treating ASD.

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Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle

Current Molecular Pharmacology ◽

10.2174/1874467213666200319125109 ◽

2020 ◽

Vol 14 (2) ◽

pp. 170-174

Author(s):

Koichi Kawada ◽

Nobuyuki Kuramoto ◽

Seisuke Mimori

Keyword(s):

Autism Spectrum Disorder ◽

Endoplasmic Reticulum ◽

Environmental Factors ◽

Endoplasmic Reticulum Stress ◽

Synapse Formation ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Neurodevelopmental Disease ◽

Number Of Patients ◽

The Brain

: Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors. In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine-glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.

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FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09358-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Reymundo Lozano ◽

Catherine Gbekie ◽

Paige M. Siper ◽

Shubhika Srivastava ◽

Jeffrey M. Saland ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Medical Assessment ◽

Forkhead Box ◽

Organ Systems ◽

Practice Parameters ◽

Assessment And Monitoring ◽

Multidisciplinary Group ◽

The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

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Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil

Viruses ◽

10.3390/v13010001 ◽

2020 ◽

Vol 13 (1) ◽

pp. 1

Author(s):

Andréia Veras Gonçalves ◽

Demócrito de B. Miranda-Filho ◽

Líbia Cristina Rocha Vilela ◽

Regina Coeli Ferreira Ramos ◽

Thalia V. B. de Araújo ◽

...

Keyword(s):

Optic Nerve ◽

Viral Infections ◽

Case Series ◽

Optic Nerve Hypoplasia ◽

Endocrine Dysfunction ◽

Careful Monitoring ◽

Early Puberty ◽

Growth Impairment ◽

Appropriate Treatment ◽

The Brain

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common—and clinically important—endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.

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025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽

10.1093/sleep/zsab072.024 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A11-A12

Author(s):

Carolyn Jones ◽

Randall Olson ◽

Alex Chau ◽

Peyton Wickham ◽

Ryan Leriche ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Prefrontal Cortex ◽

Early Life ◽

Autism Spectrum ◽

Prairie Vole ◽

Sleep Disruption ◽

Glutamatergic Synapses ◽

The Brain ◽

Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

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LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Neurodevelopmental Disorders ◽

Neurodevelopmental Disorder ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

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