Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats

2016 ◽  
Vol 29 (5) ◽  
pp. 309-314 ◽  
Author(s):  
Freja Bertelsen ◽  
Arne Møller ◽  
Davide Folloni ◽  
Kim Ryun Drasbek ◽  
Jørgen Scheel-Krüger ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Receptor Binding ◽  
Partial Agonist ◽  
Autism Spectrum ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Receptor System ◽  
Gaba System ◽  
Key Factor ◽  
Muscimol Binding

ObjectivePrenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA.MethodWe performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation.ResultPrenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding.ConclusionWe observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.

scholarly journals Melatonin MT1 and MT2 Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle

2019 ◽  
Vol 20 (10) ◽  
pp. 2452 ◽  
Author(s):  
Martha López-Canul ◽  
Seung Hyun Min ◽  
Luca Posa ◽  
Danilo De Gregorio ◽  
Annalida Bedini ◽  
...  
Keyword(s):  
Body Temperature ◽  
Receptor Antagonist ◽  
Partial Agonist ◽  
Receptor Subtypes ◽  
Dark Phase ◽  
Light Phase ◽  
Dark Cycle ◽  
Simultaneous Activation ◽  
Type 3 ◽  
G Protein Coupled

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT1 and MT2, but also through an MLT type-3 receptor (MT3). However, the role of MLT receptor subtypes in thermoregulation is still unknown. We have thus investigated the effects of selective and non-selective MLT receptor agonists/antagonists on body temperature (Tb) in rats across the 12/12-h light–dark cycle. Rectal temperature was measured every 15 min from 4:00 a.m. to 9:30 a.m. and from 4:00 p.m. to 9:30 p.m., following subcutaneous injection of each compound at either 5:00 a.m. or 5:00 p.m. MLT (40 mg/kg) had no effect when injected at 5 a.m., whereas it decreased Tb during the light phase only when injected at 5:00 p.m. This effect was blocked by the selective MT2 receptor antagonist 4P-PDOT and the non-selective MT1/MT2 receptor antagonist, luzindole, but not by the α1/MT3 receptors antagonist prazosin. However, unlike MLT, neither the selective MT1 receptor partial agonist UCM871 (14 mg/kg) nor the selective MT2 partial agonist UCM924 (40 mg/kg) altered Tb during the light phase. In contrast, UCM871 injected at 5:00 p.m. increased Tb at the beginning of the dark phase, whereas UCM924 injected at 5:00 a.m. decreased Tb at the end of the dark phase. These effects were blocked by luzindole and 4P-PDOT, respectively. The MT3 receptor agonist GR135531 (10 mg/kg) did not affect Tb. These data suggest that the simultaneous activation of both MT1 and MT2 receptors is necessary to regulate Tb during the light phase, whereas in a complex but yet unknown manner, they regulate Tb differently during the dark phase. Overall, MT1 and MT2 receptors display complementary but also distinct roles in modulating circadian fluctuations of Tb.

scholarly journals Sensory over-responsivity is related to GABAergic inhibition in thalamocortical circuits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily T. Wood ◽  
Kaitlin K. Cummings ◽  
Jiwon Jung ◽  
Genevieve Patterson ◽  
Nana Okada ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Sensory Information ◽  
Network Connectivity ◽  
Sensory Stimulation ◽  
Autism Spectrum ◽  
Future Research ◽  
Resonance Spectroscopy ◽  
Gamma Aminobutyric Acid ◽  
Sensory Stimuli ◽  
Brain Responses

AbstractSensory over-responsivity (SOR), extreme sensitivity to or avoidance of sensory stimuli (e.g., scratchy fabrics, loud sounds), is a highly prevalent and impairing feature of neurodevelopmental disorders such as autism spectrum disorders (ASD), anxiety, and ADHD. Previous studies have found overactive brain responses and reduced modulation of thalamocortical connectivity in response to mildly aversive sensory stimulation in ASD. These findings suggest altered thalamic sensory gating which could be associated with an excitatory/inhibitory neurochemical imbalance, but such thalamic neurochemistry has never been examined in relation to SOR. Here we utilized magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects. Although there were no diagnostic group differences in neurochemical concentrations in either region, within the ASD group, SOR severity correlated negatively with thalamic GABA (r = −0.48, p < 0.05) and positively with somatosensory glutamate (r = 0.68, p < 0.01). Further, in the ASD group, thalamic GABA concentration predicted altered connectivity with regions previously implicated in SOR. These variations in GABA and associated network connectivity in the ASD group highlight the potential role of GABA as a mechanism underlying individual differences in SOR, a major source of phenotypic heterogeneity in ASD. In ASD, abnormalities of the thalamic neurochemical balance could interfere with the thalamic role in integrating, relaying, and inhibiting attention to sensory information. These results have implications for future research and GABA-modulating pharmacologic interventions.

scholarly journals Preliminary Results Regarding Sleep in a Zebrafish Model of Autism Spectrum Disorder

2021 ◽  
Vol 11 (5) ◽  
pp. 556
Author(s):  
Madalina Andreea Robea ◽  
Alin Ciobica ◽  
Alexandrina-Stefania Curpan ◽  
Gabriel Plavan ◽  
Stefan Strungaru ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Valproic Acid ◽  
Social Behavior ◽  
Antiepileptic Drug ◽  
Alternative Model ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Zebrafish Model ◽  
Developmental Defects

Autism spectrum disorder (ASD) is one of the most salient developmental neurological diseases and remarkable similarities have been found between humans and model animals of ASD. A common method of inducing ASD in zebrafish is by administrating valproic acid (VPA), which is an antiepileptic drug that is strongly linked with developmental defects in children. In the present study we replicated and extended the findings of VPA on social behavior in zebrafish by adding several sleep observations. Juvenile zebrafish manifested hyperactivity and an increase in ASD-like social behaviors but, interestingly, only exhibited minimal alterations in sleep. Our study confirmed that VPA can generate specific ASD symptoms, indicating that the zebrafish is an alternative model in this field of research.

scholarly journals Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder

2021 ◽  
Author(s):  
Viktor Román ◽  
Nika Adham ◽  
Andrew G. Foley ◽  
Lynsey Hanratty ◽  
Bence Farkas ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Partial Agonist ◽  
Social Play ◽  
Autism Spectrum ◽  
Social Recognition ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Exposure Model ◽  
Behavioral Deficits

Abstract Rationale Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. Objectives The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. Methods To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. Results Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. Conclusions In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.

scholarly journals Evaluation of 16S rRNA primer sets for characterisation of microbiota in paediatric patients with autism spectrum disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. Palkova ◽  
A. Tomova ◽  
G. Repiska ◽  
K. Babinska ◽  
B. Bokor ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
16S Rrna ◽  
Dna Amplification ◽  
Disease Status ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Sequencing Analysis ◽  
Key Factor ◽  
Health And Disease ◽  
Primer Sets

AbstractAbstract intestinal microbiota is becoming a significant marker that reflects differences between health and disease status also in terms of gut-brain axis communication. Studies show that children with autism spectrum disorder (ASD) often have a mix of gut microbes that is distinct from the neurotypical children. Various assays are being used for microbiota investigation and were considered to be universal. However, newer studies showed that protocol for preparing DNA sequencing libraries is a key factor influencing results of microbiota investigation. The choice of DNA amplification primers seems to be the crucial for the outcome of analysis. In our study, we have tested 3 primer sets to investigate differences in outcome of sequencing analysis of microbiota in children with ASD. We found out that primers detected different portion of bacteria in samples especially at phylum level; significantly higher abundance of Bacteroides and lower Firmicutes were detected using 515f/806r compared to 27f/1492r and 27f*/1495f primers. So, the question is whether a gold standard of Firmicutes/Bacteroidetes ratio is a valuable and reliable universal marker, since two primer sets towards 16S rRNA can provide opposite information. Moreover, significantly higher relative abundance of Proteobacteria was detected using 27f/1492r. The beta diversity of sample groups differed remarkably and so the number of observed bacterial genera.

059 Daridorexant: A dual, equipotent, and insurmountable antagonist of both orexin-1 and orexin-2 receptors

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A25-A25
Author(s):  
Celia Mueller Grandjean ◽  
Manon Kiry ◽  
Catherine Vaillant ◽  
Oliver Nayler ◽  
John Gatfield
Keyword(s):  
Calcium Release ◽  
Brain Activity ◽  
Specific Treatment ◽  
Receptor Occupancy ◽  
Kinetic Properties ◽  
Receptor Subtypes ◽  
Residence Times ◽  
Binding Assays ◽  
Receptor System ◽  
Highly Effective

Abstract Introduction The orexin neuropeptide–receptor system is a central sleep and wake regulator in the brain. The two orexin receptor subtypes, OX1R and OX2R, are expressed either alone or together in all major wake-promoting brain areas. OX1R and OX2R activation by orexins causes elevation of intracellular calcium, which enhances synaptic transmission in secondary, monoaminergic wake- and arousal-promoting neurotransmitter circuits. Orexin receptor antagonists represent a novel and specific treatment of insomnia, which is different from classical therapy that more broadly inhibits brain activity via GABAA activation. Here we describe the molecular pharmacology of daridorexant, an orexin receptor antagonist which has proven highly effective in improving sleep and daytime functioning in insomnia patients. Methods Orexin-A(OxA)-induced calcium release assays in OX1R- and OX2R-expressing recombinant cell lines were applied to measure the antagonistic potency and kinetic properties of daridorexant in functional assays. Whole-cell competitive binding assays, using an orthosteric tracer were employed to determine the Ki of daridorexant. Comparisons were made with suvorexant and lemborexant. Results In OxA-induced calcium release assays with 2-h pre-incubation time, daridorexant displayed apparent Kb values of 0.5 nM (OX1R) and 0.8 nM (OX2R) with insurmountable antagonism on both receptors, demonstrating equipotent and highly effective functional inhibition of both receptor subtypes. On-target residence times of daridorexant (37oC) expressed as receptor occupancy half-lives (ROt1/2) were 4 min (OX1R) and 8 min (OX2R). In binding assays, daridorexant behaved as highly potent orthosteric antagonist. Also suvorexant behaved as dual insurmountable antagonist at OX1R/OX2R (appKb=0.7nM/1.0nM; ROt1/2=9 min/6 min) and as potent orthosteric antagonist in binding assays. Interestingly, lemborexant displayed a different interaction profile at OX1R/OX2R (appKb=13nM/0.4nM, ROt1/2&lt;2min/&lt;2min), i.e. it behaved as preferential OX2R antagonist with a very short on-target residence time and little insurmountability. Conclusion Daridorexant displays the desired target interaction profile of a dual, equipotent, and insurmountable antagonist of both OX1R and OX2R, which ensures equally efficient inhibition of both arousal-/wake-promoting receptor subtypes. Daridorexant′s on-target residence times are long enough to cause insurmountable inhibition, but short enough to avoid pharmacodynamic effects after drug elimination. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

scholarly journals Glix 13, a New Drug Acting on Glutamatergic Pathways in Children and Animal Models of Autism Spectrum Disorders

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Annamaria Chiara Santini ◽  
Giovanna Maria Pierantoni ◽  
Raffaele Gerlini ◽  
Rosamaria Iorio ◽  
Yinka Olabinjo ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Partial Agonist ◽  
Receptor Gene ◽  
Expression Patterns ◽  
Bioinformatic Analysis ◽  
Autism Spectrum ◽  
Receptor Modulator ◽  
Therapeutic Procedures ◽  
Significant Enrichment ◽  
Glutamatergic Pathways

Recently standardized diagnostic instruments have been developed in diagnostic and therapeutic procedures for Autism Spectrumv Disorders (ASD). According to the DSM-5 criteria, individuals with ASD must show symptoms from early childhood. These symptoms are communication deficits and restricted, repetitive patterns of behaviour. It was recently described by Bioinformatic analysis that 99 modified genes were associated with human autism. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor gene family was identified among these. Using ultrasonic vocalizations, it was demonstrated that genetic variation has a direct impact on the expression of social interactions. It has been proposed that specific alleles interact with a social reward process in the adolescent mouse modifying their social interaction and their approach toward each other. In this review we report that the monoclonal antibody-derived tetrapeptide GLYX-13 was found to act as an N-methyl-D-aspartate receptor modulator and possesses the ability to readily cross the blood brain barrier. Treatment with the NMDAR glycine site partial agonist GLYX-13 rescued the deficit in the animal model. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism in autistic children.

Changes in serotonin-induced potentials during spinal cord development

1993 ◽  
Vol 69 (4) ◽  
pp. 1338-1349 ◽  
Author(s):  
L. Ziskind-Conhaim ◽  
B. S. Seebach ◽  
B. X. Gao
Keyword(s):  
Spinal Cord ◽  
Direct Action ◽  
Membrane Resistance ◽  
Ventral Horn ◽  
Repetitive Firing ◽  
Lumbar Spinal Cord ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Spinal Neurons ◽  
Lumbar Spinal

1. Motoneuron responses to serotonin (5-hydroxytryptamine, 5-HT), and the growth pattern of 5-HT projections into the ventral horn were studied in the isolated spinal cord of embryonic and neonatal rats. 2. 5-HT projections first appeared in lumbar spinal cord at days 16-17 of gestation (E16-E17) and were localized in the lateral and ventral funiculi. By E18, the projections had grown into the ventral horn, and at 1-2 days after birth they were in close apposition to motoneuron somata. 3. At E16-E17, slow-rising depolarizing potentials of 1-4 mV were recorded intracellularly in lumbar motoneurons in response to bath application of 5-HT. These potentials were not apparent after E18; at that time 5-HT generated long-lasting depolarizations with an average amplitude of 6 mV, and an increase of 11% in membrane resistance. Starting at E18, 5-HT also induced high-frequency fast-rising potentials that were blocked by antagonists of glutamate, gamma-aminobutyric acid, and glycine. 4. Motoneuron responses to 5-HT increased significantly after birth, when 5-HT produced an average depolarization of 19 mV and repetitive firing of action potentials. 5. Tetrodotoxin and high Mg2+ did not reduce the amplitude of the long-lasting depolarizations, which suggested that they were produced by direct action of 5-HT on motoneuron membrane. 6. At all developmental ages, 5-HT reduced the amplitude of dorsal root-evoked potentials. The suppressed responses were neither due to 5-HT-induced depolarization nor the result of a decrease in motoneuron excitability. 7. The pharmacological profile of 5-HT-induced potentials was studied with the use of various agonists and antagonists of 5-HT. The findings indicated that the actions of 5-HT on spinal neurons were mediated via multiple 5-HT receptor subtypes. 8. Our results suggested that 5-HT excited spinal neurons before 5-HT projections grew into the ventral horn. The characteristics of 5-HT-induced potentials changed, however, at the time when the density of 5-HT projections increased in the motor nuclei.

scholarly journals The Proliferation of Dentate Gyrus Progenitors in the Ferret Hippocampus by Neonatal Exposure to Valproic Acid

2021 ◽  
Vol 15 ◽  
Author(s):  
Kazuhiko Sawada ◽  
Shiori Kamiya ◽  
Ichio Aoki
Keyword(s):  
Valproic Acid ◽  
Cerebral Cortex ◽  
Magnetic Resonance ◽  
Dentate Gyrus ◽  
Structural Changes ◽  
S100 Protein ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Magnetic Resonance Images ◽  
Neonatal Exposure

Prenatal and neonatal exposure to valproic acid (VPA) is associated with human autism spectrum disorder (ASD) and can alter the development of several brain regions, such as the cerebral cortex, cerebellum, and amygdala. Neonatal VPA exposure induces ASD-like behavioral abnormalities in a gyrencephalic mammal, ferret, but it has not been evaluated in brain regions other than the cerebral cortex in this animal. This study aimed to facilitate a comprehensive understanding of brain abnormalities induced by developmental VPA exposure in ferrets. We examined gross structural changes in the hippocampus and tracked proliferative cells by 5-bromo-2-deoxyuridine (BrdU) labeling following VPA administration to ferret infants on postnatal days (PDs) 6 and 7 at 200 μg/g of body weight. Ex vivo short repetition time/time to echo magnetic resonance imaging (MRI) with high spatial resolution at 7-T was obtained from the fixed brain of PD 20 ferrets. The hippocampal volume estimated using MRI-based volumetry was not significantly different between the two groups of ferrets, and optical comparisons on coronal magnetic resonance images revealed no differences in gross structures of the hippocampus between VPA-treated and control ferrets. BrdU-labeled cells were observed throughout the hippocampus of both two groups at PD 20. BrdU-labeled cells were immunopositive for Sox2 (&gt;70%) and almost immunonegative for NeuN, S100 protein, and glial fibrillary acidic protein. BrdU-labeled Sox2-positive progenitors were abundant, particularly in the subgranular layer of the dentate gyrus (DG), and were denser in VPA-treated ferrets. When BrdU-labeled Sox2-positive progenitors were examined at 2 h after the second VPA administration on PD 7, their density in the granular/subgranular layer and hilus of the DG was significantly greater in VPA-treated ferrets compared to controls. The findings suggest that VPA exposure to ferret infants facilitates the proliferation of DG progenitors, supplying excessive progenitors for hippocampal adult neurogenesis to the subgranular layer.

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