scholarly journals Cholinergic and Noradrenergic Modulation of Corticothalamic Synaptic Input From Layer 6 to the Posteromedial Thalamic Nucleus in the Rat

2021 ◽  
Vol 15 ◽  
Author(s):  
Syune Nersisyan ◽  
Marek Bekisz ◽  
Ewa Kublik ◽  
Björn Granseth ◽  
Andrzej Wróbel
Keyword(s):  
Failure Rate ◽  
Pulse Train ◽  
Acetylcholine Receptors ◽  
Thalamic Nucleus ◽  
Cortical Layer ◽  
Muscarinic Acetylcholine Receptors ◽  
Frequency Dependent ◽  
Postsynaptic Potentials ◽  
Noradrenergic Modulation

Cholinergic and noradrenergic neuromodulation of the synaptic transmission from cortical layer 6 of the primary somatosensory cortex to neurons in the posteromedial thalamic nucleus (PoM) was studied using an in vitro slice preparation from young rats. Cholinergic agonist carbachol substantially decreased the amplitudes of consecutive excitatory postsynaptic potentials (EPSPs) evoked by a 20 Hz five pulse train. The decreased amplitude effect was counteracted by a parallel increase of synaptic frequency-dependent facilitation. We found this modulation to be mediated by muscarinic acetylcholine receptors. In the presence of carbachol the amplitudes of the postsynaptic potentials showed a higher trial-to-trial coefficient of variation (CV), which suggested a presynaptic site of action for the modulation. To substantiate this finding, we measured the failure rate of the excitatory postsynaptic currents in PoM cells evoked by “pseudominimal” stimulation of corticothalamic input. A higher failure-rate in the presence of carbachol indicated decreased probability of transmitter release at the synapse. Activation of the noradrenergic modulatory system that was mimicked by application of norepinephrine did not affect the amplitude of the first EPSP evoked in the five-pulse train, but later EPSPs were diminished. This indicated a decrease of the synaptic frequency-dependent facilitation. Treatment with noradrenergic α-2 agonist clonidine, α-1 agonist phenylephrine, or β-receptor agonist isoproterenol showed that the modulation may partly rely on α-2 adrenergic receptors. CV analysis did not suggest a presynaptic action of norepinephrine. We conclude that cholinergic and noradrenergic modulation act as different variable dynamic controls for the corticothalamic mechanism of the frequency-dependent facilitation in PoM.

scholarly journals Structure and selectivity engineering of the M1 muscarinic receptor toxin complex

Science ◽  
2020 ◽  
Vol 369 (6500) ◽  
pp. 161-167 ◽  
Author(s):  
Shoji Maeda ◽  
Jun Xu ◽  
Francois Marie N. Kadji ◽  
Mary J. Clark ◽  
Jiawei Zhao ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Tertiary Structures ◽  
Venom Toxin ◽  
Natural Toxins ◽  
Subtype Specificity ◽  
Snake Venom Toxin ◽  
M1 Muscarinic ◽  
Subtype Selective

Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein–coupled receptor modulators.

scholarly journals Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus

2015 ◽  
Vol 113 (7) ◽  
pp. 2408-2419 ◽  
Author(s):  
J. Josh Lawrence ◽  
Heikki Haario ◽  
Emily F. Stone
Keyword(s):  
Pyramidal Cell ◽  
Acetylcholine Receptors ◽  
Temporal Dynamics ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Calcium Transient ◽  
Muscarinic Acetylcholine Receptors ◽  
Presynaptic Calcium

Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5–12 Hz) and gamma (20–80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability ( pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.

Neural architecture of the electrosensory lateral line lobe: adaptations for coincidence detection, a sensory searchlight and frequency-dependent adaptive filtering

1999 ◽  
Vol 202 (10) ◽  
pp. 1243-1253 ◽  
Author(s):  
N.J. Berman ◽  
L. Maler
Keyword(s):  
Lateral Line ◽  
Activity Patterns ◽  
Pyramidal Cells ◽  
Coincidence Detection ◽  
Weakly Electric Fish ◽  
In Vivo Studies ◽  
Frequency Dependent ◽  
Postsynaptic Potentials

The electrosensory lateral line lobe (ELL) of weakly electric fish is the only nucleus that receives direct input from peripheral electroreceptor afferents. This review summarises the neurotransmitters, receptors and second messengers identified in the intrinsic circuitry of the ELL and the extrinsic descending direct and indirect feedback pathways, as revealed by recent in vitro and in vivo studies. Several hypotheses of circuitry function are examined on this basis and on the basis of recent functional evidence: (1) fast primary afferent excitatory postsynaptic potentials (EPSPs) and fast granule cell 2 GABAA inhibitory postsynaptic potentials (IPSPs) suggest the involvement of basilar pyramidal cells in coincidence detection; (2) voltage-dependent EPSPs and IPSPs, dendritic spike bursts and frequency-dependent synaptic facilitation support a sensory searchlight role for the direct feedback pathway; and (3) the contributions of distal and proximal inhibition, anti-Hebbian plasticity and beam versus isolated fiber activity patterns are discussed with reference to an adaptive spatio-temporal filtering role for the indirect descending pathway.

scholarly journals Control of Cardiac Function in vivo with a Light-Regulated Drug

2018 ◽  
Author(s):  
Fabio Riefolo ◽  
Carlo Matera ◽  
Aida Garrido-Charles ◽  
Alexandre M. J. Gomila ◽  
Luca Agnetta ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mammalian Cells ◽  
Acetylcholine Receptors ◽  
Genetic Manipulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Muscarinic Acetylcholine ◽  
First Time

<p>Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between <i>cis</i> and <i>trans</i> configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated <i>in vitro</i> photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function <i>in vivo</i> in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.</p>

scholarly journals Novel Analgesic Agents Obtained by Molecular Hybridization of Orthosteric and Allosteric Ligands

2019 ◽  
Author(s):  
Carlo Matera ◽  
Lisa Flammini ◽  
Fabio Riefolo ◽  
Giuseppe Domenichini ◽  
Marco De Amici ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Functional Characterization ◽  
Unmet Need ◽  
Muscarinic Acetylcholine Receptors ◽  
Molecular Hybridization ◽  
Bioactive Substances ◽  
Pharmacological Agents ◽  
Nociceptive Transmission ◽  
Analgesic Agents

AbstractDespite the high incidence of acute and chronic pain in the general population, the efficacy of currently available medications is unsatisfactory. Insufficient management of pain has a profound impact on the quality of life and can have serious physical, psychological, social, and economic consequences. This unmet need reflects a failure to develop novel classes of analgesic drugs with superior clinical properties and lower risk of abuse. Nevertheless, recent advances in our understanding of the neurobiology of pain are offering new opportunities for developing different therapeutic approaches. Among those, the activation of M2 muscarinic acetylcholine receptors, which play a key role in the cholinergic regulation of the nociceptive transmission, constitutes one of the most promising strategies. We have recently developed a small library of novel pharmacological agents by merging the structures of known orthosteric and allosteric muscarinic ligands through their molecular hybridization, an emerging approach in medicinal chemistry based on the combination of pharmacophoric moieties of different bioactive substances to produce a new compound with improved pharmacological properties. Herein we report the functional characterization of the new ligands in vitro and the assessment of their efficacy as analgesic agents and tolerability in mice. This work provides new insights for the development and optimization of novel muscarinic hybrid compounds for the management of pain.

Temporally distinct mechanisms of use-dependent depression at inhibitory synapses in the rat hippocampus in vitro

1994 ◽  
Vol 72 (1) ◽  
pp. 121-130 ◽  
Author(s):  
N. A. Lambert ◽  
W. A. Wilson
Keyword(s):  
Acetylcholine Receptors ◽  
Interstimulus Interval ◽  
Gabab Receptor ◽  
Muscarinic Acetylcholine Receptors ◽  
Rat Hippocampus ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Gamma Aminobutyric Acid ◽  
Independent Components

1. Gamma-aminobutyric acid-B (GABAB) autoreceptor-dependent and -independent components of paired-pulse depression (PPD) at inhibitory synapses in area CA3 of the rat hippocampus were studied using whole-cell recording techniques. Inhibitory fibers were activated directly in the presence of the ionotropic glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3,dione (20 microM) and D-2-amino-5-phosphonovalerate (20 microM). 2. When pairs of monosynaptic inhibitory postsynaptic currents (eIPSCs) were evoked with an interstimulus interval of 200 ms, the amplitude of the second response (eIPSC2) was depressed when compared with the first (eIPSC1). The GABAB receptor agonist baclofen (10 microM) depressed both responses, but eIPSC1 was depressed more than eIPSC2, resulting in PPD that was comparatively smaller. Addition of the GABAB receptor antagonist CGP 55845A (1 microM) completely reversed depression of eIPSC1 by baclofen and increased the amplitude of eIPSC2 above the control value, such that PPD in the combination of baclofen and CGP 55845A was equivalent to that in baclofen alone. The ratio eIPSC2/eIPSC1 was 0.64 under control conditions, 0.77 in the presence of baclofen, and 0.79 in the presence of baclofen and CGP 55845A. These results demonstrate the existence of two components of PPD at inhibitory synapses, one that depends on activation of GABAB autoreceptors (GABAB receptor-dependent PPD) and one that does not (GABAB receptor-independent PPD). 3. When the number of inhibitory fibers activated was lowered by decreasing the stimulus intensity, eIPSC2/eIPSC1 was 0.76 under control conditions, 0.75 in the presence of baclofen, and 0.76 in the presence of baclofen and CGP 55845A. These results indicate that GABAB receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABAB receptor-independent PPD does not. 4. The time-courses of the GABAB-dependent and -independent components of PPD were compared by varying the interstimulus interval in the absence and presence of CGP 55845A. GABAB-dependent PPD was maximal at an interstimulus interval of 100 ms and was undetectable at 1 s. In contrast, GABAB-independent PPD was maximal at 5 ms and 1 s, was slightly less pronounced at intermediate intervals (50–200 ms), and was present at intervals as long as 5 s. 5. GABAB-independent PPD was not blocked by antagonists at opioid receptors (10 microM naloxone) or muscarinic acetylcholine receptors (10 microM atropine). GABAB-independent PPD could not be accounted for by a decrease in driving force because of Cl- redistribution.(ABSTRACT TRUNCATED AT 400 WORDS)

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