scholarly journals The α6 GABAA Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 175
Author(s):  
Roberto Cadeddu ◽  
Daniel E. Knutson ◽  
Laura J. Mosher ◽  
Stefanos Loizou ◽  
Karen Odeh ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Mouse Models ◽  
Neurodevelopmental Disorder ◽  
D1 Receptor ◽  
Allosteric Modulators ◽  
Serious Adverse Events ◽  
Prefrontal Cortical ◽  
Skf 82958 ◽  
Extrapyramidal Effects ◽  
Dopaminergic Antagonists

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABAA receptors containing α6 subunits (α6 GABAARs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for α6 GABAARs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to α6 GABAAR PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.

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.

scholarly journals Elevated Expression of SLC6A4 Encoding the Serotonin Transporter (SERT) in Gilles de la Tourette Syndrome

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 86
Author(s):  
Mathis Hildonen ◽  
Amanda M. Levy ◽  
Christina Dahl ◽  
Victoria A. Bjerregaard ◽  
Lisbeth Birk Møller ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Serotonin Transporter ◽  
Neurodevelopmental Disorder ◽  
Control Group ◽  
Obsessive Compulsive ◽  
Expression Levels ◽  
Compulsive Disorder ◽  
Hyperactivity Disorder ◽  
Elevated Expression ◽  
Gene Expression Levels

Gilles de la Tourette syndrome (GTS) is a complex neurodevelopmental disorder characterized by motor and vocal tics. Most of the GTS individuals have comorbid diagnoses, of which obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD) are the most common. Several neurotransmitter systems have been implicated in disease pathogenesis, and amongst these, the dopaminergic and the serotonergic pathways are the most widely studied. In this study, we aimed to investigate whether the serotonin transporter (SERT) gene (SLC6A4) was differentially expressed among GTS individuals compared to healthy controls, and whether DNA variants (the SERT-linked polymorphic region 5-HTTLPR, together with the associated rs25531 and rs25532 variants, and the rare Ile425Val variant) or promoter methylation of SLC6A4 were associated with gene expression levels or with the presence of OCD as comorbidity. We observed that SLC6A4 expression is upregulated in GTS individuals compared to controls. Although no specific genotype, allele or haplotype was overrepresented in GTS individuals compared to controls, we observed that the LAC/LAC genotype of the 5-HTTLPR/rs25531/rs25532 three-locus haplotype was associated with higher SLC6A4 mRNA expression levels in GTS individuals, but not in the control group.

scholarly journals Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3799
Author(s):  
Tim J. Fyfe ◽  
Peter J. Scammells ◽  
J. Robert Lane ◽  
Ben Capuano
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Intrinsic Activity ◽  
Optical Isomers ◽  
Allosteric Modulators ◽  
Disease States ◽  
Starting Point ◽  
Significant Difference ◽  
Optically Pure ◽  
Allosteric Properties

(1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D1R, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of 2 for the development of D1R PAMs with superior allosteric properties.

scholarly journals Daily oscillation of the excitation/inhibition ratio is disrupted in two mouse models of autism

2021 ◽  
Author(s):  
Michelle Bridi ◽  
Nancy Luo ◽  
Grace Kim ◽  
Caroline O'Ferrall ◽  
Ruchit Oatel ◽  
...  
Keyword(s):  
Mouse Models ◽  
Sensory Processing ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Behavioral State ◽  
Wild Type ◽  
Inhibitory Synaptic Transmission ◽  
Sleep Timing ◽  
Per Se ◽  
Daily Oscillation

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder involving sensory processing abnormalities. Alterations to the balance between excitation and inhibition (E/I ratio) are postulated to underlie behavioral phenotypes in ASD patients and mouse models. However, in primary visual cortex (V1) of wild type mice, the E/I ratio is not a fixed value, but rather oscillates across the 24h day. Therefore, we hypothesized that the E/I oscillation, rather than the overall E/I ratio, may be disrupted in ASD mouse models. To this end, we measured the E/I ratio in Fmr1 KO and BTBR mice, models of syndromic and idiopathic ASD, respectively. We found that the E/I ratio is dysregulated in both models, but in different ways: the oscillation is flattened in Fmr1 KO and phase-shifted in BTBR mice. These phenotypes cannot be explained by altered sleep timing, which was largely normal in both lines. Furthermore, we found that E/I dysregulation occurs due to alterations in both excitatory and inhibitory synaptic transmission in both models. These findings provide a crucial perspective on the E/I ratio in ASD, suggesting that ASD phenotypes may be produced by a mismatch of E/I to the appropriate behavioral state, rather than alterations to overall E/I levels per se.

scholarly journals Temporal discounting in adolescents and adults with Tourette syndrome

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253620
Author(s):  
Canan Beate Schüller ◽  
Ben Jonathan Wagner ◽  
Thomas Schüller ◽  
Juan Carlos Baldermann ◽  
Daniel Huys ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Positive Reinforcement ◽  
Intertemporal Choice ◽  
Neurodevelopmental Disorder ◽  
Temporal Discounting ◽  
Hyperbolic Discounting ◽  
Developmental Trajectory ◽  
Adult Patients ◽  
Control Functions ◽  
Male Subjects

Tourette syndrome is a neurodevelopmental disorder associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity. In this study, we examine whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference for smaller-but-sooner over larger-but-later rewards. We assessed intertemporal choice in two studies including nineteen adolescents (age: mean[sd] = 14.21[±2.37], 13 male subjects) and twenty-five adult patients (age: mean[sd] = 29.88 [±9.03]; 19 male subjects) with Tourette syndrome and healthy age- and education matched controls. Computational modeling using exponential and hyperbolic discounting models via hierarchical Bayesian parameter estimation revealed reduced temporal discounting in adolescent patients, and no evidence for differences in adult patients. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. Specifically, adolescents might show attenuated discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. Future studies would benefit from a longitudinal approach to further elucidate the developmental trajectory of these effects.

Dopamine D1 receptor mRNA and receptor levels in the striatum of MPTP monkeys chronically treated with SKF-82958

1999 ◽  
Vol 378 (3) ◽  
pp. 259-263 ◽  
Author(s):  
Richard Grondin ◽  
Martin Goulet ◽  
Marc Morissette ◽  
Paul J Bédard ◽  
Thérèse Di Paolo
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Receptor Mrna ◽  
Skf 82958

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

A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome

2014 ◽  
pp. 1 ◽  
Author(s):  
Donald L. Gilbert ◽  
Cathy L. Budman ◽  
Harvey S. Singer ◽  
Roger Kurlan ◽  
Richard E. Chipkin
Keyword(s):  
Receptor Antagonist ◽  
Tourette Syndrome ◽  
D1 Receptor ◽  
D1 Receptor Antagonist

scholarly journals Age-dependent differences in functional brain networks are atypical in Tourette syndrome

2020 ◽  
Author(s):  
Ashley N. Nielsen ◽  
Caterina Gratton ◽  
Soyoung Kim ◽  
Jessica A. Church ◽  
Kevin J. Black ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Tourette Syndrome ◽  
Time Course ◽  
Neurodevelopmental Disorder ◽  
Developmental Differences ◽  
Functional Networks ◽  
Functional Neuroanatomy ◽  
Brain Structure And Function ◽  
Functional Brain Networks ◽  
And Function

AbstractTourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. TS is complex, with symptoms that involve sensory, motor, and top-down control processes and that fluctuate over the course of development. While many have studied atypical brain structure and function associated with TS, the neural substrates supporting the complex range and time-course of symptoms is largely understudied. Here, we used functional connectivity MRI to examine functional networks across the whole-brain in children and adults with TS. To investigate the functional neuroanatomy of childhood and adulthood TS, we separately considered the sets of connections within each functional network and those between each pair of functional networks. We tested whether developmental stage (child, adult), diagnosis (TS, control), or an interaction between these factors was present among these connections. We found that developmental changes for most functional networks in TS were unaltered (i.e., developmental differences in TS were similar to those in typically developing children and adults). However, there were several within-network and cross-network connections that exhibited either “divergent” or “attenuated” development in TS. Connections involving the somatomotor, cingulo-opercular, auditory, dorsal attention, and default mode networks diverged from typical development in TS, demonstrating enhanced functional connectivity in adulthood TS. In contrast, connections involving the basal ganglia, thalamus, cerebellum, auditory, visual, reward, and ventral attention networks showed attenuated developmental differences in TS. These results suggest that adulthood TS is characterized by increased functional connectivity among functional networks that support cognitive control and attention, which may be implicated in suppressing, producing, and attending to tics. In contrast, subcortical systems that have been implicated in the initiation and production of tics may be immature in adulthood TS. Jointly, our results reveal how several cortical and subcortical functional networks interact and differ across development in TS.

scholarly journals Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways

2019 ◽  
Author(s):  
S. Jesse Lopez ◽  
Benjamin I. Laufer ◽  
Ulrika Beitnere ◽  
Elizabeth L. Berg ◽  
Jill L. Silverman ◽  
...  
Keyword(s):  
Systems Biology ◽  
Wnt Signaling ◽  
Mouse Models ◽  
Rat Model ◽  
Angelman Syndrome ◽  
Gene Networks ◽  
Neurodevelopmental Disorder ◽  
Postnatal Brain ◽  
Parent Of Origin ◽  
The Brain

AbstractThe genomically imprinted UBE3A gene encodes a E3 ubiquitin ligase whose loss from the maternal allele leads to the neurodevelopmental disorder Angelman syndrome. However, the mechanisms by which loss of maternal UBE3A contribute to severe neurodevelopmental phenotypes are poorly understood. Previous studies of UBE3A function have focused on mouse models or single targets, but these approaches do not accurately reflect the complexity of imprinted gene networks in the brain nor the systems-level cognitive dysfunctions in Angelman syndrome. We therefore utilized a systems biology approach to better elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9 engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring derived from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, when compared to wild-type sex-matched littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype, and time (P2, P9) was investigated through transcriptome (RNA-seq of cortex and hypothalamus) and methylome (whole genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring correlated with postnatal age that were enriched in developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment, and splicing. Furthermore, using this novel rat model, we showed that loss of the paternally expressed Ube3a antisense transcript resulted inboth unique and overlapping dysregulated gene pathways, predominantly at the level of differential methylation, when compared to loss of maternal Ube3a. Together, these results provide the most holistic examination to date of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.Author SummaryThe neurodevelopmental disorder Angelman syndrome is caused by loss of UBE3A from the maternal chromosome. UBE3A is a genomically imprinted gene, which results in parent-of-origin specific expression of a protein from the mother and a noncoding RNA from the father. While mouse models have been useful in investigating diverse roles for UBE3A, their partial mutations are of limited utility for investigating parental imprinting effects or identifying a complete list of downstream differences in gene pathways relevant to developing therapies for Angelman syndrome. To address this limitation, we utilized a novel rat model with a CRISPR/Cas9 engineered full UBE3A deletion and systems biology approaches to better understand how UBE3A loss affects early postnatal brain development. We discovered that UBE3A loss has widespread effects on many important neuronal and cellular pathways and uncovered interesting interactions between maternal and paternal genes that were not previously considered. Taken together, our findings provide the most comprehensive view of UBE3A’s influences in the brain, which are relevant to the understanding and development of treatments for Angelman syndrome and related neurodevelopmental disorders.

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