scholarly journals Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

2018 ◽  
Author(s):  
Michaela Fenckova ◽  
Lenke Asztalos ◽  
Pavel Cizek ◽  
Euginia L. Singgih ◽  
Laura E.R. Blok ◽  
...  
Keyword(s):  
De Novo ◽  
Cholinergic Neurons ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Inhibitory Neurons ◽  
Molecular Processes ◽  
Simons Simplex Collection ◽  
Id Genes ◽  
Gene Ontologies

AbstractBackgroundAlthough habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood.MethodsWe manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.ResultsWe identified more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.ConclusionsOur work demonstrates the relevance of habituation learning to autism, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.

scholarly journals Choline Transporter regulates olfactory habituation via a neuronal triad of excitatory, inhibitory and mushroom body neurons

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009938
Author(s):  
Runa Hamid ◽  
Hitesh Sonaram Sant ◽  
Mrunal Nagaraj Kulkarni
Keyword(s):  
Cholinergic Neurons ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Choline Transporter ◽  
Memory Processing ◽  
Stimulus Suppression ◽  
Incoming Stimulus

Choline is an essential component of Acetylcholine (ACh) biosynthesis pathway which requires high-affinity Choline transporter (ChT) for its uptake into the presynaptic terminals of cholinergic neurons. Previously, we had reported a predominant expression of ChT in memory processing and storing region of the Drosophila brain called mushroom bodies (MBs). It is unknown how ChT contributes to the functional principles of MB operation. Here, we demonstrate the role of ChT in Habituation, a non-associative form of learning. Odour driven habituation traces are laid down in ChT dependent manner in antennal lobes (AL), projection neurons (PNs), and MBs. We observed that reduced habituation due to knock-down of ChT in MBs causes hypersensitivity towards odour, suggesting that ChT also regulates incoming stimulus suppression. Importantly, we show for the first time that ChT is not unique to cholinergic neurons but is also required in inhibitory GABAergic neurons to drive habituation behaviour. Our results support a model in which ChT regulates both habituation and incoming stimuli through multiple circuit loci via an interplay between excitatory and inhibitory neurons. Strikingly, the lack of ChT in MBs shows characteristics similar to the major reported features of Autism spectrum disorders (ASD), including attenuated habituation, sensory hypersensitivity as well as defective GABAergic signalling. Our data establish the role of ChT in habituation and suggest that its dysfunction may contribute to neuropsychiatric disorders like ASD.

scholarly journals Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

2021 ◽  
Author(s):  
Paul C Marcogliese ◽  
Samantha L Deal ◽  
Jonathan Andrews ◽  
J Michael Harnish ◽  
V Hemanjani Bhavana ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Candidate Genes ◽  
De Novo ◽  
Functional Characterization ◽  
Gene Discovery ◽  
Autism Spectrum ◽  
Functional Screening ◽  
Simons Simplex Collection ◽  
Spectrum Disorders

Abstract:Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through ‘humanization’ rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

scholarly journals Large mosaic copy number variations confer autism risk

2020 ◽  
Author(s):  
Maxwell A. Sherman ◽  
Rachel E. Rodin ◽  
Giulio Genovese ◽  
Caroline Dias ◽  
Alison R. Barton ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Clinical Symptoms ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosome 2 ◽  
Simons Simplex Collection ◽  
Post Mortem Brain ◽  
Significant Burden

AbstractAlthough germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.

scholarly journals Damaging Mutations are Associated with Diminished Motor Skills and IQ in Children on the Autism Spectrum

2017 ◽  
Author(s):  
Andreas Buja ◽  
Natalia Volfovsky ◽  
Abba Krieger ◽  
Catherine Lord ◽  
Alex E. Lash ◽  
...  
Keyword(s):  
Motor Skills ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Restricted Interests ◽  
Gene Target ◽  
Simons Simplex Collection ◽  
Severe Impairment ◽  
Patterns Of Behavior ◽  
Core Characteristics

SummaryIn individuals with Autism Spectrum Disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ, but not with the core characteristics of ASD: deficits in social communication and interaction, and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity, as judged by the type and its gene target. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of both), moderate (impairment mainly to motor skills) and severe (impairment of both).

scholarly journals Csmd2 is a Synaptic Transmembrane Protein that Interacts with PSD-95

2018 ◽  
Author(s):  
Mark A Gutierrez ◽  
Brett E Dwyer ◽  
Santos J Franco
Keyword(s):  
Transmembrane Protein ◽  
Copy Number Variants ◽  
Plexiform Layer ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Inhibitory Neurons ◽  
Inner Plexiform Layer ◽  
Tail Domain ◽  
Synaptic Targeting ◽  
Ribbon Synapses

AbstractMutations and copy number variants of the Cub and Sushi Multiple Domains 2 (CSMD2) gene are associated with schizophrenia and autism spectrum disorder. CSMD2 is a single-pass transmembrane protein with a large extracellular domain comprising repeats of Cub and Sushi domains. Although the biological functions of CSMD2 have not been studied, the association between CSMD2 variants and cognitive function suggest that it may have a role in brain development or function. In this study, we show that mouse Csmd2 is expressed in excitatory and inhibitory neurons in the brain. Csmd2 protein exhibits a somatodendritic localization in the neocortex and hippocampus, with smaller puncta localizing further out in the neuropil. We show that many of these Csmd2 puncta co-localize with the synaptic protein PSD-95. Using immunohistochemical and biochemical methods, we further demonstrate that Csmd2 localizes to dendritic spines and is enriched in the postsynaptic density. We also find Csmd2 at ribbon synapses of the inner plexiform layer of the retina, suggesting a broader synaptic function of Csmd2 in the central nervous system. Finally, we show that the cytoplasmic tail domain of Csmd2 interacts with synaptic scaffolding proteins of the membrane-associated guanylate kinase (MAGUK) family. The association between Csmd2 and MAGUK member PSD-95 is dependent on a PDZ-binding domain on the Csmd2 tail, which is also required for synaptic targeting of Csmd2. Together, these results point toward a function for Csmd2 in dendrites and synapses, which may account for its association with several psychiatric disorders.

scholarly journals The autism-associated gene Scn2a plays an essential role in synaptic stability and learning

2018 ◽  
Author(s):  
Perry WE Spratt ◽  
Roy Ben-Shalom ◽  
Caroline M Keeshen ◽  
Kenneth J Burke ◽  
Rebecca L Clarkson ◽  
...  
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
De Novo ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Cellular Mechanisms ◽  
Behavioral Impairments

SummaryAutism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here, we show NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons, in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic stability, even when NaV1.2 expression was disrupted late in development. Furthermore, we identified behavioral impairments in learning and sociability, paralleling observations in children with SCN2A loss. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms likely underlying circuit and behavioral dysfunction in ASD.

scholarly journals Choline Transporter regulates olfactory habituation via a neuronal triad of excitatory, inhibitory and mushroom body neurons

2020 ◽  
Author(s):  
Runa Hamid ◽  
Hitesh Sonaram Sant ◽  
Mrunal Nagaraj Kulkarni
Keyword(s):  
Cholinergic Neurons ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Choline Transporter ◽  
Memory Processing ◽  
Stimulus Suppression ◽  
Incoming Stimulus

AbstractCholine is an essential component of Acetylcholine (ACh) biosynthesis pathway which requires high-affinity Choline transporter (ChT) for its uptake into the presynaptic terminals of cholinergic neurons. Previously, we reported a predominant expression of ChT in memory processing and storing region of Drosophila brain called mushroom bodies (MB). It is unknown how ChT contributes to the functional principles of MB operation. Here, we demonstrate the role of ChT in non-associative form of learning, Habituation. Odour driven habituation traces are laid down in ChT dependent manner in antennal lobes (AL), projection neurons (PN) and MB. We observed that reduced habituation due to knockdown of ChT in MB causes hypersensitivity towards odour, suggesting that ChT also regulates incoming stimulus suppression. Importantly, we show for the first time that ChT is not unique to cholinergic neurons but is also required in inhibitory GABAergic neurons to drive habituation behaviour. Our results support a model in which ChT regulates both habituation and incoming stimuli through multiple circuit loci via an interplay between excitatory and inhibitory neurons. Strikingly, the lack of ChT in MB recapitulates major features of Autism spectrum disorders (ASD) including attenuated habituation, sensory hypersensitivity as well as defective GABAergic signalling. Our data establish the role of ChT in habituation learning and suggest that its dysfunction may contribute to neuropsychiatric disorders like ASD.

scholarly journals Damaging de novo mutations diminish motor skills in children on the autism spectrum

2018 ◽  
Vol 115 (8) ◽  
pp. E1859-E1866 ◽  
Author(s):  
Andreas Buja ◽  
Natalia Volfovsky ◽  
Abba M. Krieger ◽  
Catherine Lord ◽  
Alex E. Lash ◽  
...  
Keyword(s):  
Motor Skills ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Restricted Interests ◽  
Simons Simplex Collection ◽  
Severe Impairment ◽  
Patterns Of Behavior ◽  
Core Characteristics

In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills).

scholarly journals Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample

2019 ◽  
Vol 70 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Jian Jiao ◽  
Manxue Zhang ◽  
Pingyuan Yang ◽  
Yan Huang ◽  
Xiao Hu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Analysis Tool ◽  
Whole Exome

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. Whole-exome sequencing studies have shown that de novo single-nucleotide variations (SNVs) play an important role in sporadic ASD. The present study aimed to search for de novo SNVs using whole-exome sequencing in 59 unrelated Chinese ASD sporadic trios, and found 24 genes (including five reported ASD candidate genes CACNA1D, ACHE, YY1, TTN, and FBXO11) with de novo harmful SNVs. Five genes (CACNA1D, JAK2, ACHE, MAPK7, and PRKAG2) classified as “medium-confidence” genes were found to be related to ASD using the Phenolyzer gene analysis tool, which predicts the correlation between the candidate genes and the ASD phenotype. De novo SNVs in JAK2, MAPK7, and PRKAG2 were first found in ASD. Both JAK2 and MAPK7 were involved in the regulation of the MAPK signaling pathway. Gene co-expression and inter-gene interaction networks were constructed and gene expression data in different brain regions were further extracted, revealing that JAK2 and MAPK7 genes were associated with certain previously reported ASD genes and played an important role in early brain development. The findings of this study suggest that the aforementioned five reported ASD genes and JAK2 and MAPK7 may be related to ASD susceptibility. Further investigations of expression studies in cellular and animal models are needed to explore the mechanism underlying the involvement of JAK2 and MAPK7 in ASD.

scholarly journals Synaptic Wnt/GSK3βSignaling Hub in Autism

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mario O. Caracci ◽  
Miguel E. Ávila ◽  
Giancarlo V. De Ferrari
Keyword(s):  
De Novo ◽  
Glycogen Synthase ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Glycogen Synthase Kinase 3 ◽  
Basic Information ◽  
The Central Nervous System ◽  
Spectrum Disorders ◽  
Cell Signaling Pathways

Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak andde novovariants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β(GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3βactivity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD.

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