scholarly journals Symptomatic and Disease-Modifying Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

2021 ◽  
Author(s):  
Ashley Bernardo ◽  
Philippe Lee ◽  
Michael Marcotte ◽  
Yeunus Mian ◽  
Zubair A. Khan ◽  
...  
Keyword(s):  
Side Effects ◽  
Gabaa Receptor ◽  
Chronic Stress ◽  
Gabaa Receptors ◽  
Brain Regions ◽  
Allosteric Modulation ◽  
Neuronal Morphology ◽  
Racemic Mixture ◽  
Spine Density ◽  
Α1 Subunit

AbstractChronic stress is a major risk factor for developing depressive disorders and animal models of stress recapitulate behavioral, cellular and molecular changes that are observed in human depression. Individuals exposed to chronic stress, or patients with MDD experience mood and cognitive dysfunctions. This is in part due to neuronal shrinkage in brain regions involved in several cognitive functions such as the prefrontal cortex (PFC) and the hippocampus (HPC). Also in the context of depression and chronic stress, expression levels and function of the main inhibitory neurotransmitter GABA are reduced. Thus far, drugs targeting this GABA deficit have failed to produce beneficial effects due to broad activity at various GABA receptor subunits, including the α1-subunit, resulting in broad side effects. However, refined and selective activity at the α2/3/5-subunit is hypothesized to exert beneficial effect, devoid of side effects.Here, we show that GL-II-73 and GL-I-54 exert positive allosteric modulation at the α5, and α2/3/5-contianing GABAA receptors respectively, and that they are effective both independently and in combination. Using unpredictable chronic mild stress (UCMS) experiments in male and female C57BL/6 mice (n=12 per group), we showed that acute and chronic administration of a GL-II-73/GL-I-54 racemic mixture (termed “GL-RM”) reduced anxiety-like phenotypes and reversed a working memory deficit in UCMS exposed mice. Brains from animals receiving chronic treatment were collected and stained using a Golgi staining technique. Using stereological approaches, neuronal morphology was reconstructed and dendritic length, spine count and spine density were assessed in pyramidal neurons of the PFC and hippocampus. Chronic GL-RM rescued spine density depletions caused by UCMS at apical and basal dendrites (PFC and CA1). Interestingly, spine densities in both brain regions were correlated to cognitive performance, confirming ameliorative benefits of GL-RM.Together, results support the value of selectively targeting GABAA receptors, excluding the α1-subunit, to overcome chronic stress-induced mood symptoms and cognitive deficits, as well as detriments in neuronal morphology. This study confirm results that were observed in old mice, using a α5-selective positive allosteric modulator, and reinforce the concept that the α2/3/5-containing GABAA receptor are suitable targets for the treatment of stress-induced disorders.

Positive Allosteric Modulation at α5-GABAA Receptor Reverses Cognitive Dysfunctions and Neuronal Atrophy in Mouse Model of Chronic Stress

2021 ◽  
Vol 89 (9) ◽  
pp. S213-S214
Author(s):  
Thomas Prevot ◽  
Ashley Bernardo ◽  
Philip Lee ◽  
Michael Marcotte ◽  
Daniel Knutson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gabaa Receptor ◽  
Chronic Stress ◽  
Allosteric Modulation ◽  
Cognitive Dysfunctions

The mechanism of action of zopiclone

1995 ◽  
Vol 10 (S3) ◽  
pp. 117s-128s ◽  
Author(s):  
A Doble ◽  
T Canton ◽  
C Malgouris ◽  
JM Stutzmann ◽  
O Piot ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Mechanism Of Action ◽  
Gabaa Receptors ◽  
Channel Blocker ◽  
Allosteric Modulation ◽  
Hypnotic Drug ◽  
Benzodiazepine Binding ◽  
High Doses ◽  
Electrophysiological Methods ◽  
Α Subunits

SummaryThe mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displaces the binding of [3H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [35S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different α-subunits (BZ1 and BZ2 phenotype). Studies with protein-modifying agents (eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.

scholarly journals Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Swastik Phulera ◽  
Hongtao Zhu ◽  
Jie Yu ◽  
Derek P Claxton ◽  
Nate Yoder ◽  
...  
Keyword(s):  
Ion Channel ◽  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Rational Design ◽  
Neurological Diseases ◽  
Therapeutic Agents ◽  
Structural Studies ◽  
Mutant Forms ◽  
Receptor Assembly ◽  
Α1 Subunit

Fast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABAA receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABAA receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABAA receptors implicated in multiple neurological diseases. Despite the profound importance of heteromeric GABAA receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of a tri-heteromeric α1β1γ2SEM GABAA receptor in complex with GABA, determined by single particle cryo-EM at 3.1–3.8 Å resolution, elucidating molecular principles of receptor assembly and agonist binding. Remarkable N-linked glycosylation on the α1 subunit occludes the extracellular vestibule of the ion channel and is poised to modulate receptor assembly and perhaps ion channel gating. Our work provides a pathway to structural studies of heteromeric GABAA receptors and a framework for rational design of novel therapeutic agents.

scholarly journals Inhibitory neurosteroid reverses the dendritic spine disorder caused by gain-of-function GABAAR epilepsy variants

2021 ◽  
Author(s):  
Saad Hannan ◽  
Kamei Au ◽  
Trevor G Smart
Keyword(s):  
Dendritic Spine ◽  
Gabaa Receptors ◽  
Hippocampal Neurons ◽  
Competitive Inhibition ◽  
Spine Density ◽  
Gain Of Function ◽  
Naturally Occurring ◽  
Mechanistic Basis ◽  
Genetic Epilepsies ◽  
Α1 Subunit

GABAA receptors (GABAARs) are key orchestrators of neuronal activity and several GABAAR variants have been linked to genetic neurodevelopmental disorders (NDDs) and epilepsies. Here, we report two variants (Met263Lys, Leu267Ile) in the predominant GABAAR α1 subunit gene (GABRA1) that increase apparent receptor affinity for GABA and confer spontaneous receptor activity. These gain-of-function features are unusual because GABAAR variants are traditionally thought to cause seizures by reducing inhibitory neurotransmission. Both Met263Lys and Leu267Ile increased tonic and spontaneous GABAergic conductances in neurons revealed by competitive inhibition and channel block of GABAARs. Significantly, α1-subunit variant expression in hippocampal neurons also reduced dendritic spine density. Our results indicate that elevated GABAergic signalling can precipitate genetic epilepsies and NDDs. Furthermore, the mechanistic basis may involve the de-compartmentalisation of excitatory inputs due to the removal of dendritic spines. This aberrant structural plasticity can be reversed by the naturally-occurring, therapeutically-tractable, inhibitory neurosteroid, pregnenolone sulphate.

scholarly journals Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

2020 ◽  
Author(s):  
Patty T. Huijgens ◽  
Eelke M.S. Snoeren ◽  
Robert L. Meisel ◽  
Paul G. Mermelstein
Keyword(s):  
Brain Regions ◽  
Gonadal Hormones ◽  
Neuronal Morphology ◽  
Male Rats ◽  
Male Rat ◽  
Spine Density ◽  
Nucleus Accumbens Shell ◽  
Medial Preoptic Nucleus ◽  
Motivated Behaviors ◽  
Spine Plasticity

AbstractGonadal hormones affect neuronal morphology to ultimately regulate behavior. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA), and medial preoptic nucleus (MPN). Intact and castrated (GDX) male rats were treated with dihydrotestosterone (DHT, 1.5mg) or vehicle (oil) in 3 experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through 3D reconstruction of DiI-labeled dendritic segments. GDX decreased spine density in the MPN, which was rescued by DHT treatment. MeA spine density increased in GDX-DHT animals compared to intact-oil animals. In the NAcSh, DHT decreased spine density, and also rapidly increased the number of pCREB+ cell bodies. These findings indicate that androgen signaling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviors.

Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

2020 ◽  
Vol 20 (31) ◽  
pp. 2852-2865 ◽  
Author(s):  
Damian Bartuzi ◽  
Tomasz M. Wróbel ◽  
Agnieszka A. Kaczor ◽  
Dariusz Matosiuk
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Pain Perception ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Signaling Mechanisms ◽  
Main Target ◽  
Allosteric Sites ◽  
Biased Signaling ◽  
Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

scholarly journals Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Peng Chen ◽  
Hongyang Jing ◽  
Mingtao Xiong ◽  
Qian Zhang ◽  
Dong Lin ◽  
...  
Keyword(s):  
Neural Development ◽  
Protein Level ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Pathophysiological Mechanism ◽  
Brain Disorders ◽  
Spine Density ◽  
Genes Encoding ◽  
High Level ◽  
And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

GABAA Receptor β3 Subunit Deletion Decreases α2/3 Subunits and IPSC Duration

2003 ◽  
Vol 89 (1) ◽  
pp. 128-134 ◽  
Author(s):  
Epolia Ramadan ◽  
Zhanyan Fu ◽  
Gabriele Losi ◽  
Gregg E. Homanics ◽  
Joseph H. Neale ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Cortical Neurons ◽  
Behavioral Deficits ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Surface Staining ◽  
Α1 Subunit

Deletion of the β3 subunit of the GABAA receptor produces severe behavioral deficits and epilepsy. GABAA receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) in cortical neurons in cultures from β3 −/− mice were significantly faster than those in β3 +/+ mice and were more prolonged by zolpidem. Surface staining revealed that the number of β2/3, α2, and α3 (but not of α1) subunit-expressing neurons and the intensity of subunit clusters were significantly reduced in β3 −/− mice. Transfection of β3 −/− neurons with β3 cDNA restored β2/3, α2, and α3 subunits immunostaining and slowed mIPSCs decay. We show that the deletion of the β3 subunit causes the loss of a subset of GABAA receptors with α2 and α3 subunits while leaving a receptor population containing predominantly α1 subunit with fast spontaneous IPSC decay and increased zolpidem sensitivity.

In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid

Pharmacology ◽  
2018 ◽  
Vol 103 (1-2) ◽  
pp. 10-16 ◽  
Author(s):  
Alessia Cenani ◽  
Robert J. Brosnan ◽  
Heather K. Knych
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Water Solubility ◽  
Plasma Concentrations ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Dependent Manner ◽  
Benzeneacetic Acid

Background: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on ­GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. Methods: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, β2 and γ2s subunits. The effects of DOMBA (0.2–10 mmol/L) and propanidid (0.001–1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received ­DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. Results: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5–10 and 0.5–10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. Conclusion: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

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