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 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.

Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Chang-geng Song ◽  
Xin Kang ◽  
Fang Yang ◽  
Wan-qing Du ◽  
Jia-jia Zhang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
Interneuron Development

Abstract In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

5-HT-induced jejunal motor activity: enteric locus of action and receptor subtypes

1996 ◽  
Vol 270 (6) ◽  
pp. G992-G1000 ◽  
Author(s):  
S. Graf ◽  
S. K. Sarna
Keyword(s):  
Small Intestine ◽  
Cholinergic Neurons ◽  
Conscious State ◽  
Inhibitory Neurons ◽  
Phase Iii ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Spontaneous Phase ◽  
Giant Migrating Contractions

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and receptor subtypes involved in the regulation of jejunal contractions were investigated by close intra-arterial infusions in conscious dogs. Close intra-arterial infusions of 5-HT in short segments of the jejunum stimulated phasic contractions that were blocked completely by atropine, partially by tetrodotoxin, and not affected by hexamethonium. This response was also blocked significantly by 5-HT2A and 5-HT2C receptor antagonists but was not affected by 5-HT1A/5-HT1B, 5-HT3, and 5-HT4 receptor antagonists. Spontaneous phase III contractions were inhibited significantly by 5-HT2A and 5-HT2C receptor antagonists, not affected by 5-HT1A/5-HT1B and 5-HT3 receptor antagonists, and enhanced by 5-HT4 receptor antagonists. Repeated close intra-arterial infusions of 5-HT over several days stimulated giant migrating contractions. We conclude that in the conscious state, 5-HT acts on 5-HT2A and 5-HT2C receptors located on postsynaptic cholinergic neurons in the canine jejunum to stimulate phasic contractions and phase III activity. The 5-HT4 receptors in the canine small intestine may be localized on nonadrenergic, noncholinergic inhibitory neurons; these receptors suppress the amplitude and duration of phase III activity.

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 Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Georgia Panagiotakos ◽  
Christos Haveles ◽  
Arpana Arjun ◽  
Ralitsa Petrova ◽  
Anshul Rana ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Autism Spectrum ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Timothy Syndrome ◽  
Cortical Projection ◽  
Embryonic Mouse ◽  
Syndromic Asd

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

scholarly journals Genome-wide, integrative analysis implicates circular RNA dysregulation in autism and the corresponding circular RNA-microRNA-mRNA regulatory axes

2019 ◽  
Author(s):  
Yen-Ju Chen ◽  
Chia-Ying Chen ◽  
Te-Lun Mai ◽  
Chih-Fan Chuang ◽  
Sachin Kumar Gupta ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Circular Rna ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Mammalian Brain ◽  
Circular Rnas ◽  
Risk Genes ◽  
Genome Wide ◽  
Genes Encoding

AbstractCircular RNAs (circRNAs), a class of long non-coding RNAs, are known to be enriched in mammalian brain and neural tissues. While the effects of regulatory genetic variants on gene expression in autism spectrum disorder (ASD) have been widely reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in post-mortem brains from individuals with ASD and controls and identified 60 circRNAs and three co-regulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8,170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This result reflects the previous observation that ASD-derived organoids exhibit overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were indeed regulated by an upregulated circRNA (circARID1A) via sponging a downregulated microRNA (miR-204-3p) in human neuronal cells. We provided a systems-level view of landscape of circRNA regulatory networks in ASD cortex samples. We also provided multiple lines of evidence for the functional role of ASD for circRNA dysregulation and a rich set of ASD-associated circRNA candidates and the corresponding circRNA-miRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

Examining the Role of Language in Play Among Children With and Without Developmental Disabilities

2020 ◽  
Vol 51 (3) ◽  
pp. 795-806 ◽  
Author(s):  
Elizabeth J. Short ◽  
Rachael Cooper Schindler ◽  
Rita Obeid ◽  
Maia M. Noeder ◽  
Laura E. Hlavaty ◽  
...  
Keyword(s):  
Developmental Disabilities ◽  
Autism Spectrum ◽  
Free Play ◽  
Group Differences ◽  
Typically Developing ◽  
Play Skills ◽  
Critical Aspect ◽  
Hyperactivity Disorder ◽  
Better Than

Purpose Play is a critical aspect of children's development, and researchers have long argued that symbolic deficits in play may be diagnostic of developmental disabilities. This study examined whether deficits in play emerge as a function of developmental disabilities and whether our perceptions of play are colored by differences in language and behavioral presentations. Method Ninety-three children participated in this study (typically developing [TD]; n = 23, developmental language disorders [DLD]; n = 24, attention-deficit/hyperactivity disorder [ADHD]; n = 26, and autism spectrum disorder [ASD]; n = 20). Children were videotaped engaging in free-play. Children's symbolic play (imagination, organization, elaboration, and comfort) was scored under conditions of both audible language and no audible language to assess diagnostic group differences in play and whether audible language impacted raters' perception of play. Results Significant differences in play were evident across diagnostic groups. The presence of language did not alter play ratings for the TD group, but differences were found among the other diagnostic groups. When language was audible, children with DLD and ASD (but not ADHD) were scored poorly on play compared to their TD peers. When language was not audible, children with DLD were perceived to play better than when language was audible. Conversely, children with ADHD showed organizational deficits when language was not available to support their play. Finally, children with ASD demonstrated poor play performance regardless of whether language was audible or not. Conclusions Language affects our understanding of play skills in some young children. Parents, researchers, and clinicians must be careful not to underestimate or overestimate play based on language presentation. Differential skills in language have the potential to unduly influence our perceptions of play for children with developmental disabilities.

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

Amelioration of Carbon Tetrachloride-Induced Liver Injury by Citrus Leaf Extract

2019 ◽  
Vol 17 (4) ◽  
pp. 426-431
Author(s):  
Jin Xuezhu ◽  
Li Jitong ◽  
Nie Leigang ◽  
Xue Junlai
Keyword(s):  
Carbon Tetrachloride ◽  
Leaf Extract ◽  
Hepatic Injury ◽  
The Body ◽  
Dependent Manner ◽  
Weight Changes ◽  
Citrus Leaf ◽  
Dose Dependent ◽  
And Oxidative Stress

The main purpose of this study is to investigate the role of citrus leaf extract in carbon tetrachloride-induced hepatic injury and its potential molecular mechanism. Carbon tetrachloride was used to construct hepatic injury animal model. To this end, rats were randomly divided into 4 groups: control, carbon tetrachloride-treated, and two carbon tetrachloride + citrus leaf extract-treated groups. The results show that citrus leaf extract treatment significantly reversed the effects of carbon tetrachloride on the body weight changes and liver index. Besides, treatment with citrus leaf extract also reduced the levels of serum liver enzymes and oxidative stress in a dose-dependent manner. H&E staining and western blotting suggested that citrus leaf extract could repair liver histological damage by regulating AMPK and Nrf-2.

Microbiota, Immune System and Autism Spectrum Disorders: An Integrative Model towards Novel Treatment Options

2020 ◽  
Vol 27 (31) ◽  
pp. 5119-5136 ◽  
Author(s):  
Barbara Carpita ◽  
Donatella Marazziti ◽  
Lionella Palego ◽  
Gino Giannaccini ◽  
Laura Betti ◽  
...  
Keyword(s):  
Immune System ◽  
Familial Aggregation ◽  
Treatment Options ◽  
Autism Spectrum ◽  
Integrative Model ◽  
Neural Basis ◽  
Integrative Framework ◽  
Intermediate Phenotypes ◽  
Close Relatives

Background: Autism Spectrum Disorder (ASD) is a condition strongly associated with genetic predisposition and familial aggregation. Among ASD patients, different levels of symptoms severity are detectable, while the presence of intermediate autism phenotypes in close relatives of ASD probands is also known in literature. Recently, increasing attention has been paid to environmental factors that might play a role in modulating the relationship between genomic risk and development and severity of ASD. Within this framework, an increasing body of evidence has stressed a possible role of both gut microbiota and inflammation in the pathophysiology of neurodevelopment. The aim of this paper is to review findings about the link between microbiota dysbiosis, inflammation and ASD. Methods: Articles ranging from 1990 to 2018 were identified on PUBMED and Google Scholar databases, with keyword combinations as: microbiota, immune system, inflammation, ASD, autism, broad autism phenotype, adult. Results: Recent evidence suggests that microbiota alterations, immune system and neurodevelopment may be deeply intertwined, shaping each other during early life. However, results from both animal models and human samples are still heterogeneous, while few studies focused on adult patients and ASD intermediate phenotypes. Conclusion: A better understanding of these pathways, within an integrative framework between central and peripheral systems, might not only shed more light on neural basis of ASD symptoms, clarifying brain pathophysiology, but it may also allow to develop new therapeutic strategies for these disorders, still poorly responsive to available treatments.

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