scholarly journals Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

2021 ◽  
Author(s):  
Xavier Caubit ◽  
Paolo Gubellini ◽  
Pierre L Roubertoux ◽  
Michele Carlier ◽  
Jordan Molitor ◽  
...  
Keyword(s):  
Social Interaction ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Conditional Knockout ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Projection System ◽  
Cholinergic Interneurons ◽  
Patterns Of Behavior ◽  
Circuit Components

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

scholarly journals Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Xavier Caubit ◽  
Elise Arbeille ◽  
Dorian Chabbert ◽  
Florence Desprez ◽  
Imane Messak ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Great Majority ◽  
Bioinformatic Analysis ◽  
Autism Spectrum ◽  
Lineage Tracing ◽  
Spectrum Disorder ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Cholinergic Interneurons ◽  
Behavioral Abnormalities

Camk2a-Cre mice have been widely used to study the postnatal function of several genes in forebrain projection neurons, including cortical projection neurons (CPNs) and striatal medium-sized spiny neurons (MSNs). We linked heterozygous deletion of TSHZ3/Tshz3 gene to autism spectrum disorder (ASD) and used Camk2a-Cre mice to investigate the postnatal function of Tshz3, which is expressed by CPNs but not MSNs. Recently, single-cell transcriptomics of the adult mouse striatum revealed the expression of Camk2a in interneurons and showed Tshz3 expression in striatal cholinergic interneurons (SCINs), which are attracting increasing interest in the field of ASD. These data and the phenotypic similarity between the mice with Tshz3 haploinsufficiency and Camk2a-Cre-dependent conditional deletion of Tshz3 (Camk2a-cKO) prompted us to better characterize the expression of Tshz3 and the activity of Camk2a-Cre transgene in the striatum. Here, we show that the great majority of Tshz3-expressing cells are SCINs and that all SCINs express Tshz3. Using lineage tracing, we demonstrate that the Camk2a-Cre transgene is expressed in the SCIN lineage where it can efficiently elicit the deletion of the Tshz3-floxed allele. Moreover, transcriptomic and bioinformatic analysis in Camk2a-cKO mice showed dysregulated striatal expression of a number of genes, including genes whose human orthologues are associated with ASD and synaptic signaling. These findings identifying the expression of the Camk2a-Cre transgene in SCINs lineage lead to a reappraisal of the interpretation of experiments using Camk2a-Cre-dependent gene manipulations. They are also useful to decipher the cellular and molecular substrates of the ASD-related behavioral abnormalities observed in Tshz3 mouse models.

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

2021 ◽  
Author(s):  
Kan Yang ◽  
Yuhan Shi ◽  
Xiujuan Du ◽  
Yuefang Zhang ◽  
Shifang Shan ◽  
...  
Keyword(s):  
Social Interaction ◽  
De Novo ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genetic Components ◽  
Truncating Mutation ◽  
Synaptic Functions ◽  
Core Symptoms

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.

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

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Serap Bilge ◽  
Barış Ekici
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Interaction ◽  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Average Dose ◽  
The Core ◽  
Core Symptoms

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.

scholarly journals Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

2019 ◽  
Author(s):  
Katelyn N. Benthall ◽  
Katherine R. Cording ◽  
Alexander H.C.W. Agopyan-Miu ◽  
Emily Y. Chen ◽  
Helen S. Bateup
Keyword(s):  
Motor Learning ◽  
Motor Behavior ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Repetitive Behaviors ◽  
Cortical Activation ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway

AbstractTuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which patients frequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause changes to motor behavior in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and determined the consequences on synaptic function and motor learning. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. In addition, dSPN Tsc1 KO mice have impaired endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum, dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced cortical activation of the striatal direct pathway is a potential contributor to altered motor behaviors in TSC.

scholarly journals RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains

2021 ◽  
Author(s):  
Chengwen Wei ◽  
Mengwen Sun ◽  
Xiaoxuan Sun ◽  
Hu Meng ◽  
Qiongwei Li ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Neuronal Migration ◽  
Rho Gtpase ◽  
Sh3 Domain ◽  
Autism Spectrum ◽  
Conditional Knockout ◽  
Cell Surface Expression ◽  
Projection Neurons ◽  
Radial Migration ◽  
Myosin X

AbstractThe radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

scholarly journals THE CHARACTERISTICS OF AUTISM ASPERGER SYNDROME IN MARK HADDON’S NOVEL THE CURIOUS INCIDENT OF THE DOG IN THE NIGHT

2020 ◽  
Vol 1 (2) ◽  
pp. 112-119
Author(s):  
Dhitya Anggreni ◽  
M. Manugeren
Keyword(s):  
Social Interaction ◽  
Asperger Syndrome ◽  
Developmental Disorder ◽  
Social Activity ◽  
Autism Spectrum ◽  
The Novel ◽  
Grand Theory ◽  
Library Research ◽  
Patterns Of Behavior ◽  
Language Attitude

This article is concerned with the protagonist of the story suffering from Asperger Syndrome. He finds difficulty in social interaction, be it appearance, language, attitude, or thinking. In addition, he has got an intelligent ability to interpret objects around him well. He has also the ability to make patterns of activities that he does every time. The whole analysis is conducted by means of qualitative research method supported by library research. The grand theory used is on autism, picturing Asperger Syndrome as an autism spectrum disorder on the high functioning end; referred to as “dash of autism”. Asperger syndrome, also known as Asperger’s, is a developmental disorder characterized by significant difficulties in social interaction and nonverbal communication, along with restricted and repetitive patterns of behavior and interests. The results show that the protagonist of the novel has got some significant features of Asperger Syndrome: Lacking of Social Activity, Ability of Interpreting Object, and Ability to Set Routine Patterns.

scholarly journals Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration

2018 ◽  
Vol 29 (5) ◽  
pp. 2148-2159 ◽  
Author(s):  
Anna Hoerder-Suabedissen ◽  
Kim V Korrell ◽  
Shuichi Hayashi ◽  
Alexander Jeans ◽  
Denise M O Ramirez ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Hippocampal Neurons ◽  
Vesicle Fusion ◽  
Conditional Knockout ◽  
Snare Complex ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Markers Of Inflammation ◽  
Synaptic Vesicle Fusion

Abstract Synaptosomal associated protein 25 kDa (SNAP25) is an essential component of the SNARE complex regulating synaptic vesicle fusion. SNAP25 deficiency has been implicated in a variety of cognitive disorders. We ablated SNAP25 from selected neuronal populations by generating a transgenic mouse (B6-Snap25tm3mcw (Snap25-flox)) with LoxP sites flanking exon5a/5b. In the presence of Cre-recombinase, Snap25-flox is recombined to a truncated transcript. Evoked synaptic vesicle release is severely reduced in Snap25 conditional knockout (cKO) neurons as shown by live cell imaging of synaptic vesicle fusion and whole cell patch clamp recordings in cultured hippocampal neurons. We studied Snap25 cKO in subsets of cortical projection neurons in vivo (L5—Rbp4-Cre; L6—Ntsr1-Cre; L6b—Drd1a-Cre). cKO neurons develop normal axonal projections, but axons are not maintained appropriately, showing signs of swelling, fragmentation and eventually complete absence. Onset and progression of degeneration are dependent on the neuron type, with L5 cells showing the earliest and most severe axonal loss. Ultrastructural examination revealed that cKO neurites contain autophagosome/lysosome-like structures. Markers of inflammation such as Iba1 and lipofuscin are increased only in adult cKO cortex. Snap25 cKO can provide a model to study genetic interactions with environmental influences in several disorders.

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 Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

2019 ◽  
Author(s):  
Mounia Bensaid ◽  
Yann Loe-Mie ◽  
Aude-Marie Lepagnol-Bestel ◽  
Wenqi Han ◽  
Gabriel Santpere ◽  
...  
Keyword(s):  
High Risk ◽  
Cortical Neurons ◽  
De Novo ◽  
Deep Layer ◽  
Autism Spectrum ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Linkage Region ◽  
Genomic Architecture ◽  
A Genome

ABSTRACTAutism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype.Significance StatementThe human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type–specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

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