scholarly journals Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

2022 ◽  
Author(s):  
Stamatina Tzanoulinou ◽  
Stefano Musardo ◽  
Alessandro Contestabile ◽  
Sebastiano Bariselli ◽  
Giulia Casarotto ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Transient Receptor Potential Vanilloid ◽  
Acute Inflammatory Response ◽  
Social Deficits ◽  
Neurodevelopmental Disease

AbstractMutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/− mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

scholarly journals Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

2021 ◽  
Author(s):  
Stamatina Tzanoulinou ◽  
Stefano Musardo ◽  
Alessandro Contestabile ◽  
Sebastiano Bariselli ◽  
Giulia Casarotto ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ex Vivo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Neurodevelopmental Disease ◽  
Environmental Interactions ◽  
Potential Risk Factors

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

scholarly journals Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Ellegood ◽  
S. P. Petkova ◽  
A. Kinman ◽  
L. R. Qiu ◽  
A. Adhikari ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Altered Expression ◽  
Developmental Growth ◽  
And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

2017 ◽  
Vol 114 (30) ◽  
pp. 8119-8124 ◽  
Author(s):  
Karen J. Parker ◽  
Ozge Oztan ◽  
Robin A. Libove ◽  
Raena D. Sumiyoshi ◽  
Lisa P. Jackson ◽  
...  
Keyword(s):  
Social Functioning ◽  
Placebo Treatment ◽  
Primary Outcome Measure ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Responsiveness ◽  
Social Deficits ◽  
Double Blind ◽  
Children With Asd ◽  
Social Abilities

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients’ underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6–12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial’s primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

scholarly journals Social Deficits and Repetitive Behaviors Are Improved by Early Postnatal Low-Dose VPA Intervention in a Novel shank3-Deficient Zebrafish Model

2021 ◽  
Vol 15 ◽  
Author(s):  
Chunxue Liu ◽  
Yi Wang ◽  
Jingxin Deng ◽  
Jia Lin ◽  
Chunchun Hu ◽  
...  
Keyword(s):  
Low Dose ◽  
Social Preference ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Neural Tube Closure ◽  
Synaptic Proteins ◽  
Therapeutic Window ◽  
Social Deficits ◽  
Zebrafish Model ◽  
Expression Levels

Mutations of the SHANK3 gene are found in some autism spectrum disorder (ASD) patients, and animal models harboring SHANK3 mutations exhibit a variety of ASD-like behaviors, presenting a unique opportunity to explore the underlying neuropathological mechanisms and potential pharmacological treatments. The histone deacetylase (HDAC) valproic acid (VPA) has demonstrated neuroprotective and neuroregenerative properties, suggesting possible therapeutic utility for ASD. Therefore, SHANK3-associated ASD-like symptoms present a convenient model to evaluate the potential benefits, therapeutic window, and optimal dose of VPA. We constructed a novel shank3-deficient (shank3ab–/–) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including of core ASD-like behaviors, as well as molecular analyses of synaptic proteins expression levels. Furthermore, different VPA doses and treatment durations were examined for effects on ASD-like phenotypes. Compared to wild types (WTs), shank3ab–/– zebrafish exhibited greater developmental mortality, more frequent abnormal tail bending, pervasive developmental delay, impaired social preference, repetitive swimming behaviors, and generally reduced locomotor activity. The expression levels of synaptic proteins were also dramatically reduced in shank3ab–/– zebrafish. These ASD-like behaviors were attenuated by low-dose (5 μM) VPA administered from 4 to 8 days post-fertilization (dpf), and the effects persisted to adulthood. In addition, the observed underexpression of grm5, encoding glutamate metabotropic receptor 5, was significantly improved in VPA-treated shank3ab–/– zebrafish. We report for the first time that low-dose VPA administered after neural tube closure has lasting beneficial effects on the social deficits and repetitive behavioral patterns in shank3-deficient ASD model zebrafish. These findings provide a promising strategy for ASD clinical drug development.

scholarly journals Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

2020 ◽  
Vol 318 (4) ◽  
pp. L723-L741 ◽  
Author(s):  
Qian Yu ◽  
Daoxin Wang ◽  
Xiaoting Wen ◽  
Xumao Tang ◽  
Di Qi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Response ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Endothelial Barrier ◽  
Mouse Serum ◽  
Transient Receptor Potential Vanilloid ◽  
Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

scholarly journals Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model

2018 ◽  
Vol 19 (10) ◽  
pp. 3226 ◽  
Author(s):  
Amin Al-awar ◽  
Nikoletta Almási ◽  
Renáta Szabó ◽  
Istvan Takacs ◽  
Zsolt Murlasits ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Oral Treatment ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dipeptidyl Peptidase 4 ◽  
Regional Ischemia ◽  
Transient Receptor

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.

scholarly journals Comprehensive phenotyping of group III and IV muscle afferents in mouse

2013 ◽  
Vol 109 (9) ◽  
pp. 2374-2381 ◽  
Author(s):  
Michael P. Jankowski ◽  
Kristofer K. Rau ◽  
Katrina M. Ekmann ◽  
Collene E. Anderson ◽  
H. Richard Koerber
Keyword(s):  
Spinal Cord ◽  
Functional Properties ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Muscle Afferents ◽  
Transient Receptor Potential Vanilloid ◽  
Sensory Afferents ◽  
Group Iii ◽  
Concentration Levels

While much is known about the functional properties of cutaneous nociceptors, relatively little is known about the comprehensive functional properties of group III and IV muscle afferents. We have developed a mouse ex vivo forepaw muscle, median and ulnar nerve, dorsal root ganglion (DRG), spinal cord recording preparation to examine the functional response properties, neurochemical phenotypes, and spinal projections of individual muscle afferents. We found that the majority of group III and IV muscle afferents were chemosensitive (52%) while only 34% responded to mechanical stimulation and fewer (32%) responded to thermal stimuli. The chemosensitive afferents could be grouped into those that responded to a “low”-metabolite mixture containing amounts of lactate and ATP at pH 7.0 simulating levels observed in muscle during exercise (metaboreceptors) and a “high”-metabolite mixture containing lactic acid concentrations and ATP at pH 6.6 mimicking levels observed during ischemic contractions (metabo-nociceptors). While the majority of the metabo-nociceptive fibers responding to the higher concentration levels were found to contain acid-sensing ion channel 3 (ASIC3) and/or transient receptor potential vanilloid type 1 (TRPV1), metaboreceptors responding to the lower concentration levels lacked these receptors. Anatomically, group III muscle afferents were found to have projections into laminae I and IIo, and deeper laminae in the spinal cord, while all functional types of group IV muscle afferents projected primarily into both laminae I and II. These results provide novel information about the variety of sensory afferents innervating the muscle and provide insight into the types of fibers that may exhibit plasticity after injuries.

scholarly journals Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

2020 ◽  
Author(s):  
Jacob Ellegood ◽  
Stela P Petkova ◽  
Adrienne Kinman ◽  
Lily R Qiu ◽  
Ayanna Wade ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Social Deficits ◽  
Repetitive Behaviours ◽  
Developmental Growth ◽  
Reported Data ◽  
Full Investigation

Abstract Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B) , a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created validated to characterize and define neuroanatomical, behavioural and tran­scriptional phenotypes. Neuroanatomy was assess ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones.Results - Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, during neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Limitations – The behaviour and the neuroimaging analysis were done on separate cohorts of mice, which does not allow a direct correlation between the imaging and behavioural findings. Conclusions – This study represents a full investigation of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1

2020 ◽  
Vol 318 (2) ◽  
pp. F298-F314 ◽  
Author(s):  
Luke Grundy ◽  
Ashlee Caldwell ◽  
Sonia Garcia Caraballo ◽  
Andelain Erickson ◽  
Gudrun Schober ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Transient Receptor Potential Vanilloid ◽  
Receptor Subtypes ◽  
Urothelial Cells ◽  
Bladder Pain ◽  
Bladder Distension ◽  
Bladder Afferents

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited “silent afferents” that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes ( Hrh1– Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.

Sign in / Sign up

Export Citation Format

Share Document