scholarly journals Defects of myelination are common pathophysiology in syndromic and idiopathic autism spectrum disorder

2017 ◽  
Author(s):  
BaDoi N. Phan ◽  
Stephanie Cerceo Page ◽  
Morganne N. Campbell ◽  
Joseph F. Bohlen ◽  
Courtney L. Thaxton ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Postmortem Brain ◽  
Protein Levels ◽  
Gene Sets ◽  
Significant Enrichment ◽  
Transcriptional Changes ◽  
Syndromic Asd

AbstractAutism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Ptenm3m4/m3m4, Mecp2KO). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder

2017 ◽  
pp. 103-119 ◽  
Author(s):  
Saša Peter ◽  
Chris I. De Zeeuw ◽  
Tobias M. Boeckers ◽  
Michael J. Schmeisser
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

2013 ◽  
Vol 12 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Tiffany D. Rogers ◽  
Price E. Dickson ◽  
Eric McKimm ◽  
Detlef H. Heck ◽  
Dan Goldowitz ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Prefrontal Cortical

scholarly journals Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

2021 ◽  
Vol 14 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Amy Cheung ◽  
Kensuke Futai
Keyword(s):  
Autism Spectrum Disorder ◽  
Molecular Mechanism ◽  
Strong Association ◽  
Critical Role ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Synaptic Signaling ◽  
Syndromic Asd ◽  
Chemical Synapses ◽  
And Function

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.

Diminished social interaction incentive contributes to social deficits in mouse models of autism spectrum disorder

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Benjamin Rein ◽  
Zhen Yan ◽  
Zi‐Jun Wang
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Interaction ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Social Deficits

scholarly journals Phenotypic subgrouping and multi-omics analyses reveal reduced diazepam-binding inhibitor (DBI) protein levels in autism spectrum disorder with severe language impairment

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0214198 ◽  
Author(s):  
Chatravee Pichitpunpong ◽  
Surangrat Thongkorn ◽  
Songphon Kanlayaprasit ◽  
Wasana Yuwattana ◽  
Waluga Plaingam ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Language Impairment ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Protein Levels

scholarly journals Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

2017 ◽  
Vol 17 (1) ◽  
pp. 4-22 ◽  
Author(s):  
P.A. Kabitzke ◽  
D. Brunner ◽  
D. He ◽  
P.A. Fazio ◽  
K. Cox ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Comprehensive Analysis ◽  
Spectrum Disorder

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

scholarly journals Comprehensive Analysis of Two Shank3 and the Cacna1c Mouse Models of Autism Spectrum Disorder

2016 ◽  
Author(s):  
Patricia Kabitzke ◽  
Daniela Brunner ◽  
Dansha He ◽  
Pamela A. Fazio ◽  
Kimberly Cox ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Gene Mutations ◽  
Behavioral Effect ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Therapeutic Interventions ◽  
General Anxiety ◽  
Background Strain ◽  
Negative Results

AbstractTo expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng’s Shank3tm2Gfng model, hereafter Shank3/F, Jiang’s Shank3tm1Yhj model, hereafter Shank3/J, and the Cacna1c deletion model. The Shank3/F and Shank3/J models mimick gene mutations associated with Phelan-Mcdermid syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. The current study utilizes both standard and novel, computer-vision based behavioral tests, the same methdology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. Overall, some but not all behaviors replicated published findings. Those that replicated, such as social behavior and overgrooming in Shank3 models, also tended to be milder than previous reports. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, Shank3/F but not Shank3/J KO or Cacna1c HET showed differences in sensory-gating. Discrepancies in our current results from previous reports may be dependent on subtle differences in testing conditions, housing enrichment, or background strain. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

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