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)

Synaptic transmission between ventrolateral funiculus axons and lumbar motoneurons in the isolated spinal cord of the neonatal rat

1994 ◽  
Vol 72 (5) ◽  
pp. 2406-2419 ◽  
Author(s):  
M. Pinco ◽  
A. Lev-Tov
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Short Latency ◽  
Neonatal Rat ◽  
Gamma Aminobutyric Acid ◽  
Long Latency ◽  
Ventrolateral Funiculus

1. We studied the projections of ventrolateral funiculus (VLF) axons to lumbar motoneurons in the in vitro spinal cord preparation of 1- to 6-day-old rats using extracellular and sharp-electrode intracellular recordings. 2. Ipsilateral and contralateral VLF projections to lumbar motoneurons (L4-L5) could be activated in the neonatal rat by stimulation of the surgically peeled VLF at the rostral (L1-L2) and caudal lumbar (L6) cord. Motoneurons were activated ipsilaterally through short- and long-latency projections in all cases and contralaterally through long-latency projections in most cases. 3. Suppression of the excitatory components of VLF postsynaptic potentials (PSPs) by application of the specific antagonists of N-methyl D-aspartate (NMDA) and non-NMDA receptors, 2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquin-oxaline-2,3-dione (CNQX), revealed depolarizing PSPs that could be reversed at -55 to -60 mV by injection of depolarizing current steps to the motoneurons. These depolarizing PSPs were blocked by addition of strychnine and bicuculline and are therefore suggested to be glycine and gamma-aminobutyric acid-A (GABAA) receptor-mediated inhibitory PSPs. The identity of a small (< or = 0.2 mV) residual depolarizing component that persisted in the presence of APV, CNQX, strychnine, and bicuculline remains to be determined. 4. Short-latency excitatory PSPs (EPSPs) could be resolved from the ipsilaterally elicited VLF PSPs after the reduction of the polysynaptic activity in the preparation by administration of mephenesin, which was followed by suppression of the glycine and GABAA receptor-mediated components of the PSPs by bath application of strychnine and bicuculline. The latencies of these EPSPs were similar to those of the monosynaptic dorsal root afferent EPSPs recorded from the same motoneurons. These short-latency VLF EPSPs were shortened by the NMDA antagonist APV and revealed an NMDA receptor-mediated component after administration of the non-NMDA receptor antagonist CNQX. Addition of the GABAB receptor agonist L-(-) baclofen or the glutamate analogue L-2-amino-4-phosphonobutyric acid (L-AP4) attenuated the pharmacologically resolved short-latency EPSPs.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

scholarly journals Effects of Mlx-8, a phospholipase A2 from Brazilian coralsnake Micrurus lemniscatus venom, on muscarinic acetylcholine receptors in rat hippocampus

2020 ◽  
Vol 26 ◽  
Author(s):  
Roberta Tancredi Francesco dos Santos ◽  
Marcelo Florencio Passos Silva ◽  
Rafael Marques Porto ◽  
Ivo Lebrun ◽  
Luís Roberto de Camargo Gonçalves ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Rat Hippocampus ◽  
Muscarinic Acetylcholine

Differential ontogenesis of presynaptic and postsynaptic GABAB inhibition in rat somatosensory cortex

1993 ◽  
Vol 70 (1) ◽  
pp. 448-452 ◽  
Author(s):  
A. Fukuda ◽  
I. Mody ◽  
D. A. Prince
Keyword(s):  
Somatosensory Cortex ◽  
Gabab Receptor ◽  
Age Groups ◽  
Brain Slices ◽  
Gaba Release ◽  
Equilibrium Potential ◽  
Gamma Aminobutyric Acid ◽  
Postnatal Maturation ◽  
Rat Somatosensory Cortex

1. The postnatal maturation of gamma-aminobutyric acid (GABA)B receptor-mediated presynaptic inhibition was studied in brain slices of rat somatosensory cortex maintained in vitro. Patchclamp techniques were used to record whole-cell inhibitory post-synaptic currents from layer II-III neurons in animals from postnatal days (P) 7-24. Monosynaptic inhibitory postsynaptic currents (IPSCs) were evoked after N-methyl-D-aspartate (NMDA) and non-NMDA type glutamate receptors had been blocked by D-amino-phosphonovaleric acid (D-AP5, 20 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), respectively. These IPSCs were solely mediated by postsynaptic GABAA receptors because they were abolished by bicuculline (10 microM), reversed polarity near the chloride equilibrium potential, and were recorded with electrodes that contained Cs+ to block postsynaptic GABAB responses. 2. When pairs of stimuli separated by intervals of 0.1-10 s were used to evoke IPSCs, the second response was depressed, an effect that was maximal at 300 ms. Evoked IPSCs were also depressed by baclofen (10 microM). The paired pulse depression (PPD) of monosynaptic IPSCs was decreased or eliminated by 2-OH-saclofen (200 microM). These findings indicate that PPD of monosynaptic IPSCs was due to presynaptic GABAB receptor-mediated inhibition of GABA release. 3. There were no significant differences in the amounts of PPD in neurons from different age groups (P7-10, P12-17, P22-24) at any interstimulus interval tested (0.1-10 s).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Estrogen on Muscarinic Acetylcholine Receptors in the Rat Hippocampus

2004 ◽  
Vol 80 (6) ◽  
pp. 379-386 ◽  
Author(s):  
Camila C. Cardoso ◽  
Renato T.S. Pereira ◽  
Cristiane A. Koyama ◽  
Catarina S. Porto ◽  
Fernando M.F. Abdalla
Keyword(s):  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Rat Hippocampus ◽  
Muscarinic Acetylcholine

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 Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xinyan Li ◽  
Wenting Chen ◽  
Xian Huang ◽  
Wei Jing ◽  
Tongmei Zhang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Early Stage ◽  
Long Term Potentiation ◽  
Delay Of Gratification ◽  
Lateral Septum ◽  
Self Control ◽  
Inhibitory Neurons ◽  
System Level ◽  
Inhibitory Synapses ◽  
Gamma Aminobutyric Acid

Abstract Background Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. Methods We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. Results We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. Conclusions These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD.

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.

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