scholarly journals Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome

2018 ◽  
Vol 115 (42) ◽  
pp. 10744-10749 ◽  
Author(s):  
Wei-Hsiang Huang ◽  
David C. Wang ◽  
William E. Allen ◽  
Matthew Klope ◽  
Hailan Hu ◽  
...  
Keyword(s):  
Social Interaction ◽  
Mouse Model ◽  
Behavioral Problems ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Critical Window ◽  
Genetic Mouse Model ◽  
Expression Of Genes ◽  
Syndromic Autism ◽  
Level 3

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

scholarly journals Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature

2019 ◽  
Author(s):  
Patricia Kabitzke ◽  
Diana Morales ◽  
Dansha He ◽  
Kimberly Cox ◽  
Jane Sutphen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Model Systems ◽  
Activity Levels ◽  
Phenotypic Differences ◽  
Genetic Mouse Model ◽  
Unitary Concept

3.AbstractBackgroundPhenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD.MethodsTo assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences.ResultsResults in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar.ConclusionsOur results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.

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 Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

2021 ◽  
Author(s):  
Chaojuan Yang ◽  
Yonglu Tian ◽  
Feng Su ◽  
Yangzhen Wang ◽  
Mengna Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Visual Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Local Network ◽  
V1 Neurons ◽  
Processing Deficits

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

scholarly journals Diminished cortical excitation and elevated inhibition during perceptual impairments in a mouse model of autism

2019 ◽  
Author(s):  
Joseph Del Rosario ◽  
Anderson Speed ◽  
Hayley Arrowood ◽  
Cara Motz ◽  
Machelle Pardue ◽  
...  
Keyword(s):  
Visual Perception ◽  
Mouse Model ◽  
Inhibitory Activity ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Neuron Activity ◽  
Conflicting Evidence ◽  
Inhibitory Population ◽  
Sensory Activity ◽  
Speed Accuracy

AbstractSensory impairments are a core feature of autism spectrum disorder (ASD). These impairments affect visual perception (Robertson and Baron-Cohen, 2017), and have been hypothesized to arise from imbalances in cortical excitatory and inhibitory activity (Rubenstein and Merzenich, 2003; Nelson and Valakh, 2015; Sohal and Rubenstein, 2019); however, there is little direct evidence testing this hypothesis in identified excitatory and inhibitory neurons during impairments of sensory perception. Several recent studies have examined cortical activity in transgenic mouse models of ASD (Goel et al., 2018; Antoine et al., 2019; Lazaro et al., 2019), but have provided conflicting evidence for excitatory versus inhibitory activity deficits. Here, we utilized a genetically relevant mouse model of ASD (CNTNAP2−/− knockout, KO; Arking et al., 2008; Penagarikano et al., 2011) and directly recorded putative excitatory and inhibitory population spiking in primary visual cortex (V1) while measuring visual perceptual behavior (Speed et al., 2019). We found quantitative impairments in the speed, accuracy, and contrast sensitivity of visual perception in KO mice. These impairments were simultaneously associated with elevated inhibitory and diminished excitatory neuron activity evoked by visual stimuli during behavior, along with aberrant 3 – 10 Hz oscillations in superficial cortical layers 2/3 (L2/3). These results establish that perceptual deficits relevant for ASD can arise from diminished sensory activity of excitatory neurons in feedforward layers of cortical circuits.

scholarly journals Psilocybin rescues sociability deficits in an animal model of autism

2020 ◽  
Author(s):  
Irene Mollinedo-Gajate ◽  
Chenchen Song ◽  
Marcos Sintes-Rodriguez ◽  
Tobias Whelan ◽  
Anaïs Soula ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Valproic Acid ◽  
Animal Model ◽  
Social Interaction ◽  
Mouse Model ◽  
Therapeutic Agent ◽  
Autism Spectrum ◽  
The Core ◽  
Acute Response ◽  
The Social

AbstractAutism spectrum disorder (ASD) is characterized by core deficits in social interaction. The classic serotonergic psychedelic psilocybin has been suggested as a therapeutic agent that may ameliorate in the core symptomology of ASD. We found that the acute response to psilocybin was attenuated in the prenatal valproic acid exposure mouse model of ASD, and importantly, psilocybin rescued the social behavioural abnormalities present in these ASD model mice.

scholarly journals Increased axonal bouton stability during learning in the mouse model of MECP2 duplication syndrome

2017 ◽  
Author(s):  
Ryan T. Ash ◽  
Paul G. Fahey ◽  
Jiyoung Park ◽  
Huda Y. Zoghbi ◽  
Stelios M. Smirnakis
Keyword(s):  
Motor Learning ◽  
Mouse Model ◽  
Dendritic Spine ◽  
Pyramidal Neuron ◽  
Structural Plasticity ◽  
Autism Spectrum ◽  
Wild Type ◽  
Syndromic Autism ◽  
Mecp2 Duplication Syndrome ◽  
Duplication Syndrome

ABSTRACTMECP2-duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding Methyl-CpG-binding protein 2. Mice overexpressing MECP2 demonstrate altered patterns of learning and memory, including enhanced motor learning. Previous work associated this enhanced motor learning to abnormally increased stability of dendritic spine clusters formed in the apical tuft of corticospinal, area M1, neurons during rotarod training. In the current study, we measure the structural plasticity of axonal boutons in Layer 5 (L5) pyramidal neuron projections to layer 1 of area M1 during motor learning. In wild-type mice we find that during rotarod training, bouton formation rate changes minimally, if at all, while bouton elimination rate doubles. Notably, the observed upregulation in bouton elimination with learning is absent in MECP2-duplication mice. This result provides further evidence of imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination doubles with motor learning in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor learning.SIGNIFICANCE STATEMENTAbnormal balance between synaptic stability and plasticity is a feature of several autism spectrum disorders, often corroborated by in vivo studies of dendritic spine turnover. Here we provide the first evidence that abnormally increased stability of axonal boutons, the presynaptic component of excitatory synapses, occurs during motor learning in the MECP2 duplication syndrome mouse model of autism. In contrast, in normal controls, axonal bouton elimination in L5 pyramidal neuron projections to layer 1 of area M1 doubles with motor learning. The fact that axonal projection boutons get eliminated, while corticospinal dendritic spines get consolidated with motor learning in layer 1 of area M1, suggests that structural plasticity manifestations differ across different M1 microcircuits.

scholarly journals Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involving CHRNA7

2020 ◽  
Author(s):  
Kesavan Meganathan ◽  
Ramachandran Prakasam ◽  
Dustin Baldridge ◽  
Paul Gontarz ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Er Stress ◽  
Neuronal Migration ◽  
Autism Spectrum ◽  
Emotional Dysregulation ◽  
Axonal Guidance ◽  
Inhibitory Neurons ◽  
Unrelated Control ◽  
Male And Female ◽  
Expression Of Genes

AbstractBackgroundCopy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have multiple psychiatric disorders with widely variable penetrance. However, the basis of such differential affectation remains uncharacterized.MethodsInduced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment.ResultsThe AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or the unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the AP model’s neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT, axonal guidance, and GABA receptor signaling. Interestingly, the UM model exhibited upregulated expression of genes in many of these same pathways, by comparison with both the AP and UC models, suggesting that cell intrinsic molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in the UM model. However, by contrast with the AP-specific neurodevelopmental phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity.ConclusionTogether, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the variable phenotypic penetrance seen in other individuals with 15q13.3 duplication.

scholarly journals T177. CANNABIDIOL AS A POTENTIAL PREVENTATIVE TREATMENT IN A NEUREGULIN-1 MOUSE MODEL OF SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S298-S299
Author(s):  
Gabriela Visini ◽  
Rose Chesworth ◽  
Tim Karl
Keyword(s):  
Social Interaction ◽  
Mouse Model ◽  
Open Field ◽  
Negative Symptoms ◽  
Therapeutic Potential ◽  
Sensorimotor Gating ◽  
Treatment Compliance ◽  
Brain Maturation ◽  
Western Blots ◽  
Genetic Mouse Model

Abstract Background Schizophrenia is caused by interactions between genes of predisposition and environmental insults. The main pharmacological treatments for schizophrenia are antipsychotic drugs; however, these are associated with a range of side effects (weight gain, metabolic disease, diabetes), have limited treatment compliance, and do not work for approximately 30% of patients. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise as an antipsychotic-like drug in both human and rodent studies, however its potential as a preventative drug via anti-inflammatory pathways has not yet been investigated. Brain maturation during adolescent development creates a window where CBD could potentially reverse later behavioural deficits via pathways such as anti-inflammation, and reverse the deficits caused by Δ⁹-tetrahydrocannabinol (THC), a psychoactive compound of the cannabis plant linked to the development of schizophrenia. Here we investigated the therapeutic potential of CBD administered in adolescence to protect against the development of schizophrenia-like behaviours, as well as whether CBD could protect against later sensitivity to THC. For this study we used a well-established genetic mouse model of schizophrenia (Nrg1 TM HET) that shows face, construct, and predictive validity for schizophrenia, and is also more susceptible to the effects of cannabinoids. Methods In this study, male Nrg1 TM HET mice and wild type (WT) mice were treated with 30 mg/kg of CBD or vehicle intraperitoneally for three weeks during adolescence (PND 35–60). Mice were tested CBD-free in adulthood (5–6 mo) in the open field task, which measures locomotion and anxiety (related to positive symptoms in schizophrenia); social interaction, which measures mouse interactions (relevant to negative symptoms); pre-pulse inhibition (PPI), which measures sensorimotor gating (deficits also found in schizophrenia patients); and fear conditioning, which measures associative learning and memory. Mice were then treated after one week washout with either 3 mg/kg of THC or vehicle, and run in a battery of open field, social interaction, and PPI tests. Brains and bloods were collected to investigate neuroinflammation after another week of washout. Western blots were used to investigate Iba1 levels, while ELISA was used to investigate levels of cytokines IL-10, IL-1B, and TNF-a. Results CBD treatment significantly reduced anxiety in Nrg1 TM HET mice but not WT mice, however it had no effect on locomotion in either group in the open field task. CBD treatment lowered the frequency of total social interaction in both genotypes, and reduced the frequency of social interactions of Nrg1 TM HET to WT levels. CBD reduced PPI in Nrg1 TM HET mice but not WT mice, and Nrg1 TM HET mice had lower overall PPI than WT mice. There was no effect of CBD on fear-associated memory. CBD effects on THC sensitivity in these mice are ongoing, as are brain cytokine and protein analyses. Discussion These results suggest that Nrg1 TM HET mice are more susceptible to the effects of chronic CBD in adolescence, despite a significant washout. This confirms previous data from our laboratory demonstrating increased susceptibility of Nrg1 TM HET male mice to cannabinoid constituents, and suggests persistent brain changes following adolescent exposure to CBD. Potential reasons for these persistent changes include an altered neuroinflammatory profile in Nrg1 TM HET mice. CBD has previously been shown to be anxiolytic in other studies and our results confirm its potential as an anxiolytic, particularly in our model of schizophrenia.

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