Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism

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.

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Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22147251 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7251

Author(s):

Petrilla Jayaprakash ◽

Dmytro Isaev ◽

Waheed Shabbir ◽

Dietrich E. Lorke ◽

Bassem Sadek ◽

...

Keyword(s):

Oxidative Stress ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Pathological Condition ◽

Repetitive Behaviors ◽

Social Deficits ◽

Nicotinic Acetylcholine ◽

Oxidative Stress Status ◽

Inward Currents ◽

Α7 Nachrs

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.

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Effect of Positive Allosteric Modulation of Dopamine D2 Receptors on Respiration in Mouse Models of Rett Syndrome

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.01696 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Sebastian Maletz ◽

Brandon Reid ◽

John Bissonnette ◽

Erica Levitt

Keyword(s):

Rett Syndrome ◽

Mouse Models ◽

Allosteric Modulation ◽

D2 Receptors ◽

Dopamine D2 Receptors ◽

Dopamine D2

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Somatosensorimotor and Odor Modification, Along with Serotonergic Processes Underlying the Social Deficits in BTBR T+ Itpr3tf/J and BALB/cJ Mouse Models of Autism

Neuroscience ◽

10.1016/j.neuroscience.2020.02.002 ◽

2020 ◽

Vol 445 ◽

pp. 144-162 ◽

Cited By ~ 3

Author(s):

Hiroyuki Arakawa

Keyword(s):

Mouse Models ◽

Social Deficits ◽

The Social

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705521114 ◽

2017 ◽

Vol 114 (30) ◽

pp. 8119-8124 ◽

Cited By ~ 97

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.

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Translational animal models of autism and neurodevelopmental disorders

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2012.14.3/jcrawley ◽

2012 ◽

Vol 14 (3) ◽

pp. 293-305 ◽

Cited By ~ 31

Keyword(s):

Mouse Models ◽

De Novo ◽

Single Gene ◽

Neurodevelopmental Disorder ◽

Gene Mutations ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Restricted Interests ◽

Homologous Genes ◽

Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.682054 ◽

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.

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