[43] Measurement of glial transport currents in microcultures: Application to excitatory neurotransmission

1998 ◽  
pp. 632-645 ◽  
Author(s):  
Steven Mennerick ◽  
Charles F. Zorumski
Keyword(s):  
Excitatory Neurotransmission

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

scholarly journals AMPA receptor inhibition by synaptically released zinc

2015 ◽  
Vol 112 (51) ◽  
pp. 15749-15754 ◽  
Author(s):  
Bopanna I. Kalappa ◽  
Charles T. Anderson ◽  
Jacob M. Goldberg ◽  
Stephen J. Lippard ◽  
Thanos Tzounopoulos
Keyword(s):  
Dorsal Cochlear Nucleus ◽  
Fine Tuning ◽  
Receptor Inhibition ◽  
Endogenous Modulator ◽  
Excitatory Neurotransmission ◽  
Zinc Levels ◽  
Zinc Inhibition ◽  
Endogenous Modulators ◽  
Activity Dependent

The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).

1995 ◽  
Vol 198 (7) ◽  
pp. 1621-1628 ◽  
Author(s):  
L T Buck ◽  
P E Bickler
Keyword(s):  
Cerebral Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Control Level ◽  
Chrysemys Picta ◽  
Receptor Modulation ◽  
A1 Receptor ◽  
Excitatory Neurotransmission ◽  
Similar Decrease

Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.

Fruits for Seizures? A Systematic Review on the Potential Anti- Convulsant Effects of Fruits and its Phytochemicals

2021 ◽  
Vol 19 ◽  
Author(s):  
Lee Hsien Siang ◽  
Alina Arulsamy ◽  
Yeong Keng Yoon ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Critical Appraisal ◽  
Treatment Strategies ◽  
Alternative Methods ◽  
Drug Resistant ◽  
Future Studies ◽  
Seizure Models ◽  
Epileptic Patients ◽  
Anti Oxidant ◽  
Excitatory Neurotransmission ◽  
Harmful Effects

: Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro- convulsant effects of fruits used in relation to seizures, in hopes to provide a good therapeutic reference to epileptic patients and their carers. Three databases; SCOPUS, ScienceDirect and PubMed were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit, which was attributed to the its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.

scholarly journals Mechanisms Underlying Regulation of Respiratory Pattern by Nicotine in PreBötzinger Complex

2001 ◽  
Vol 85 (6) ◽  
pp. 2461-2467 ◽  
Author(s):  
Xuesi M. Shao ◽  
Jack L. Feldman
Keyword(s):  
Respiratory Frequency ◽  
Neonatal Rat ◽  
Respiratory Pattern ◽  
Dependent Manner ◽  
Baseline Noise ◽  
Arterial Blood ◽  
Inspiratory Neurons ◽  
Excitatory Neurotransmission ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

Cholinergic neurotransmission plays a role in regulation of respiratory pattern. Nicotine from cigarette smoke affects respiration and is a risk factor for sudden infant death syndrome (SIDS) and sleep-disordered breathing. The cellular and synaptic mechanisms underlying this regulation are not understood. Using a medullary slice preparation from neonatal rat that contains the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythm generation, and generates respiratory-related rhythm in vitro, we examined the effects of nicotine on excitatory neurotransmission affecting inspiratory neurons in preBötC and on the respiratory-related motor activity from hypoglossal nerve (XIIn). Microinjection of nicotine into preBötC increased respiratory frequency and decreased the amplitude of inspiratory bursts, whereas when injected into XII nucleus induced a tonic activity and an increase in amplitude but not in frequency of inspiratory bursts from XIIn. Bath application of nicotine (0.2–0.5 μM, approximately the arterial blood nicotine concentration immediately after smoking a cigarette) increased respiratory frequency up to 280% of control in a concentration-dependent manner. Nicotine decreased the amplitude to 82% and increased the duration to 124% of XIIn inspiratory bursts. In voltage-clamped preBötC inspiratory neurons (including neurons with pacemaker properties), nicotine induced a tonic inward current of −19.4 ± 13.4 pA associated with an increase in baseline noise. Spontaneous excitatory postsynaptic currents (sEPSCs) present during the expiratory period increased in frequency to 176% and in amplitude to 117% of control values; the phasic inspiratory drive inward currents decreased in amplitude to 66% and in duration to 89% of control values. The effects of nicotine were blocked by mecamylamine (Meca). The inspiratory drive current and sEPSCs were completely eliminated by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence or absence of nicotine. In the presence of tetrodotoxin (TTX), low concentrations of nicotine did not induce any tonic current or any increase in baseline noise, nor affect the input resistance in inspiratory neurons. In this study, we demonstrated that nicotine increased respiratory frequency and regulated respiratory pattern by modulating the excitatory neurotransmission in preBötC. Activation of nicotinic acetylcholine receptors (nAChRs) enhanced the tonic excitatory synaptic input to inspiratory neurons including pacemaker neurons and at the same time, inhibited the phasic excitatory coupling between these neurons. These mechanisms may account for the cholinergic regulation of respiratory frequency and pattern.

scholarly journals Correction: Canonical Wnt3a modulates intracellular calcium and enhances excitatory neurotransmission in hippocampal neurons.

2020 ◽  
Vol 295 (27) ◽  
pp. 9265-9265
Author(s):  
Miguel E. Avila ◽  
Fernando J. Sepúlveda ◽  
Carlos F. Burgos ◽  
Gustavo Moraga-Cid ◽  
Jorge Parodi ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Hippocampal Neurons ◽  
Excitatory Neurotransmission

scholarly journals Catatonia: Clinical Overview of the Diagnosis, Treatment, and Clinical Challenges

2021 ◽  
Vol 13 (4) ◽  
pp. 570-586
Author(s):  
Amber N. Edinoff ◽  
Sarah E. Kaufman ◽  
Janice W. Hollier ◽  
Celina G. Virgen ◽  
Christian A. Karam ◽  
...  
Keyword(s):  
Sinus Thrombosis ◽  
Case Reports ◽  
Cerebral Venous Sinus Thrombosis ◽  
Definitive Treatment ◽  
Gamma Aminobutyric Acid ◽  
Medical Conditions ◽  
Motor Pathways ◽  
Nmda Receptor Encephalitis ◽  
Excitatory Neurotransmission ◽  
Clinical Overview

Catatonia is a syndrome that has been associated with several mental illness disorders but that has also presented as a result of other medical conditions. Schizophrenia and other psychiatric disorders such as mania and depression are known to be associated with catatonia; however, several case reports have been published of certain medical conditions inducing catatonia, including hyponatremia, cerebral venous sinus thrombosis, and liver transplantation. Neuroleptic Malignant Syndrome and anti-NMDA receptor encephalitis are also prominent causes of catatonia. Patients taking benzodiazepines or clozapine are also at risk of developing catatonia following the withdrawal of these medications—it is speculated that the prolonged use of these medications increases gamma-aminobutyric acid (GABA) activity and that discontinuation may increase excitatory neurotransmission, leading to catatonia. The treatment of catatonia often involves the use of benzodiazepines, such as lorazepam, that can be used in combination therapy with antipsychotics. Definitive treatment may be found with electroconvulsive therapy (ECT). Aberrant neuronal activity in different motor pathways, defective neurotransmitter regulation, and impaired oligodendrocyte function have all been proposed as the pathophysiology behind catatonia. There are many clinical challenges that come with catatonia and, as early treatment is associated with better outcomes, it becomes imperative to understand these challenges. The purpose of this manuscript is to provide an overview of these challenges and to look at clinical studies regarding the pathophysiology, diagnosis, and treatment of as well as the complications and risk factors associated with catatonia.

scholarly journals Gating the channel pore of ionotropic glutamate receptors with bacterial substrate binding proteins

2021 ◽  
Author(s):  
Max Bernhard ◽  
Bodo Laube
Keyword(s):  
Glutamate Receptors ◽  
Binding Proteins ◽  
Disulfide Bridge ◽  
Ionotropic Glutamate Receptors ◽  
Functional Coupling ◽  
Channel Pore ◽  
Channel Current ◽  
Binding Domains ◽  
Bacterial Binding ◽  
Excitatory Neurotransmission

AbstractTetrameric ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the mammalian central nervous system and are involved in learning, memory formation, and pathological processes. Based on structural and sequence similarities of the ligand-binding and channel domains of iGluR subunits to bacterial binding proteins and potassium channels, iGluRs are thought to have originally arisen from their fusion. Here we report the functional coupling of the bacterial ectoine binding protein EhuB to the channel pore-forming transmembrane domains of the bacterial GluR0 receptor by stabilization of dimeric binding domains. Insertion of a disulfide bridge in the dimer interface abolished desensitization of the channel current analogous to mammalian iGluRs. These results demonstrate the functional compatibility of bacterial binding proteins to the gate of the channel pore of an iGluR. Moreover, our results highlight the modular structure and crucial role of binding domain dimerization in the functional evolution of iGluRs.

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