Effects of general anesthetics on synaptic transmission and plasticity

2021 ◽  
Vol 19 ◽  
Author(s):  
Jimcy Platholi ◽  
Hugh C. Hemmings Jr
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Anesthetic Agent ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Synaptic Structure ◽  
Gabaergic Synapses ◽  
Voltage Gated Ion Channels ◽  
Higher Order Functions

: General anesthetics depress excitatory and/or enhance inhibitory synaptic transmission principally by modulating the function of glutamatergic or GABAergic synapses, respectively, with relative anesthetic agent-specific mechanisms. Synaptic signaling proteins, including ligand- and voltage-gated ion channels, are targeted by general anesthetics to modulate various synaptic mechanisms including presynaptic neurotransmitter release, postsynaptic receptor signaling, and dendritic spine dynamics to produce their characteristic acute neurophysiological effects. As synaptic structure and plasticity mediate higher-order functions such as learning and memory, long-term synaptic dysfunction following anesthesia may lead to undesirable neurocognitive consequences depending on specific anesthetic agent and the vulnerability of population. Here we review the cellular and molecular mechanisms of transient and persistent general anesthetic alterations of synaptic transmission and plasticity.

scholarly journals Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Gonzalo Ruiz-Pérez ◽  
Samuel Ruiz de Martín Esteban ◽  
Sharai Marqués ◽  
Noelia Aparicio ◽  
M. Teresa Grande ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Synaptic Transmission ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Genetic Inactivation ◽  
5Xfad Mouse

Abstract Background The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

Halothane-induced synaptic depression at both in vivo and in vitro reconstructed synapses between identified Lymnaea neurons

1995 ◽  
Vol 74 (6) ◽  
pp. 2604-2613 ◽  
Author(s):  
G. E. Spencer ◽  
N. I. Syed ◽  
K. Lukowiak ◽  
W. Winlow
Keyword(s):  
Synaptic Transmission ◽  
Lymnaea Stagnalis ◽  
Cell Types ◽  
Inhibitory Synapses ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Presynaptic Neuron ◽  
Novel Approach

1. In the present study we tested the ability of the general anesthetic, halothane, to affect synaptic transmission at in vivo and in vitro reconstructed peptidergic synapses between identified neurons of Lymnaea stagnalis. 2. An identified respiratory interneuron, visceral dorsal 4 (VD4), innervates a number of postsynaptic cells in the central ring ganglia of Lymnaea. Because VD4 has previously been shown to exhibit immunoreactivity for FMRFamide-related peptides, it was hypothesized that these peptides may be utilized by VD4 during synaptic transmission. In the intact, isolated CNS of Lymnaea, we have identified novel connections between VD4 and the pedal A (PeA) cells. We demonstrate that VD4 makes inhibitory connections with the PeA neurons, in particular PeA4, and that these synaptic responses are mimicked by exogenous application of FMRFamide. 3. The synaptic transmission between VD4 and the PeA cells in an intact, isolated CNS preparation was completely blocked in 2%, but not 1% halothanc. Interestingly, the postsynaptic responses (PeA) to exogenous FMRFamide were maintained in the presence of both 1 and 2% halothane. 4. To determine the specificity of the observed responses and to determine the precise synaptic site of anesthetic action, we reconstructed the VD4/PeA synapses in vitro. After isolation from their respective ganglia, both cell types extended processes and established neuritic contact. We demonstrated that not only did the presynaptic neuron reestablish the appropriate inhibitory synapses with the PeA neurons, but that the PeA cells also maintained their responsiveness to exogenous FMRFamide. 5. Superfusion of the in vitro synaptically connected VD4 and PeA cells with 2% halothane completely abolished the synaptic transmission between these cells. However, even higher concentrations of 4% halothane failed to block the responsiveness of the PeA neurons to exogenous FMRFamide. Moreover, both 1 and 2% halothane enhanced the duration of the postsynaptic response to exogenously applied FMRFamide. These data suggest that the halothane-induced depression of synaptic transmission most likely occurred at the presynaptic level. 6. This study provides the first direct evidence that peptidergic transmission in the nervous system may also be susceptible to the actions of general anesthetics. In addition, we utilized a novel approach of in vitro reconstructed synapses for studying the effects of general anesthetics on monosynaptic transmission in the absence of other synaptic influences.

Long-term Effects of Single or Multiple Neonatal Sevoflurane Exposures on Rat Hippocampal Ultrastructure

2015 ◽  
Vol 122 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Levana G. Amrock ◽  
Mathew L. Starner ◽  
Kathy L. Murphy ◽  
Mark G. Baxter
Keyword(s):  
Threshold Effect ◽  
Epidemiological Studies ◽  
Population Based ◽  
Male Rat ◽  
General Anesthetics ◽  
Long Term Effects ◽  
General Anesthetic ◽  
Synaptic Loss ◽  
Rat Pups

Abstract Background: Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology. Methods: Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13. Results: Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 ± 0.040 μm3 [mean ± SEM]) was more profound than that of a single 6-h exposure (2.280 ± 0.045 μm3, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 ± 0.017), both repeated 2-h exposures (0.479 ± 0.015) and a single 6-h exposure (0.488 ± 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001). Conclusion: This suggests a “threshold effect” for general anesthetic–induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss.

Selective Synaptic Actions of Thiopental and Its Enantiomers

2002 ◽  
Vol 96 (4) ◽  
pp. 884-892 ◽  
Author(s):  
Robert Dickinson ◽  
Sara L. M. de Sousa ◽  
William R. Lieb ◽  
Nicholas P. Franks
Keyword(s):  
Charge Transfer ◽  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Excitatory Synapses ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetic ◽  
Glutamatergic Synapses ◽  
Conflicting Evidence ◽  
Gabaergic Synapses ◽  
Gabaergic Synaptic Transmission

Background There is conflicting evidence concerning the extent to which the intravenous general anesthetic thiopental acts by enhancing inhibitory gamma-aminobutyric acid-mediated (GABAergic) synaptic transmission or by inhibiting excitatory glutamatergic transmission. Yet there are remarkably few studies on the effects of thiopental on functional synapses. In addition, the degree of stereoselectivity of thiopental acting at synapses has yet to be tested. Methods The actions of thiopental and its enantiomers on GABAergic and glutamatergic synapses were investigated using voltage clamp techniques on microisland cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks. Results Racemic thiopental markedly enhanced the charge transfer at GABAergic synapses without significantly affecting the peak of the postsynaptic current. At a surgically relevant concentration (25 microm), charge transfer was increased by approximately 230%. However, even at twice this concentration there were no significant effects on glutamatergic postsynaptic currents. At GABAergic synapses, thiopental acted stereoselectively, with the S(-) enantiomer being approximately twice as effective as the R(+) enantiomer at enhancing charge transfer. Conclusions Thiopental stereoselectively enhances inhibitory GABAergic synaptic transmission in a way that reflects animal potencies, supporting the idea that this is a principal mode of action for this drug. The absence of any effect on glutamatergic synapses at surgically relevant concentrations suggests that the inhibition of these excitatory synapses is not an important factor in producing thiopental general anesthesia.

scholarly journals Impact of Chronic BDNF Depletion on GABAergic Synaptic Transmission in the Lateral Amygdala

2019 ◽  
Vol 20 (17) ◽  
pp. 4310 ◽  
Author(s):  
Susanne Meis ◽  
Thomas Endres ◽  
Thomas Munsch ◽  
Volkmar Lessmann
Keyword(s):  
Synaptic Transmission ◽  
Long Term Potentiation ◽  
Fear Learning ◽  
Inhibitory Synapses ◽  
Lateral Amygdala ◽  
Term Potentiation ◽  
Gabaergic Synapses ◽  
Bdnf Signaling ◽  
The Impact

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABAA-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF+/−). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF+/− mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF+/− mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF+/− mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.

scholarly journals Specific nanoscale synaptic reshuffling and control of short-term plasticity following NMDAR- and P2XR-dependent Long-Term Depression

2019 ◽  
Author(s):  
Benjamin Compans ◽  
Magalie Martineau ◽  
Remco V. Klaassen ◽  
Thomas M. Bartol ◽  
Corey Butler ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Global Changes ◽  
Short Term ◽  
Long Term Depression ◽  
Term Potentiation ◽  
And Control

Long-Term Potentiation (LTP) and Long-Term Depression (LTD) of excitatory synaptic transmission are considered as cellular basis of learning and memory. These two forms of synaptic plasticity have been mainly attributed to global changes in the number of synaptic AMPA-type glutamate receptor (AMPAR) through a regulation of the diffusion/trapping balance at the PSD, exocytosis and endocytosis. While the precise molecular mechanisms at the base of LTP have been intensively investigated, the ones involved in LTD remains elusive. Here we combined super-resolution imaging technique, electrophysiology and modeling to describe the various modifications of AMPAR nanoscale organization and their effect on synaptic transmission in response to two different LTD protocols, based on the activation of either NMDA receptors or P2X receptors. While both type of LTD are associated with a decrease in synaptic AMPAR clustering, only NMDAR-dependent LTD is associated with a reorganization of PSD-95 at the nanoscale. This change increases the pool of diffusive AMPAR improving synaptic short-term facilitation through a post-synaptic mechanism. These results demonstrate that specific dynamic reorganization of synapses at the nanoscale during specific LTD paradigm allows to improve the responsiveness of depressed synapses.

scholarly journals Cellular and molecular mechanisms in the long-term action of antidepressants

2008 ◽  
Vol 10 (4) ◽  
pp. 385-400 ◽  
Keyword(s):  
Gene Expression ◽  
Synaptic Transmission ◽  
Mood Disorders ◽  
Molecular Mechanisms ◽  
Final Section ◽  
Therapeutic Action ◽  
Temporal Delay ◽  
Current Version ◽  
Lines Of Evidence

The hypotheses on the pathophysiology of depression/mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the "hypothesis of neuroplasticity". In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.

scholarly journals Neuromodulation and neuroprotective effects of chlorogenic acids in excitatory synapses of mouse hippocampal slices

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mara Yone D. Fernandes ◽  
Fernando Dobrachinski ◽  
Henrique B. Silva ◽  
João Pedro Lopes ◽  
Francisco Q. Gonçalves ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Quinic Acid ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Chlorogenic Acids ◽  
Coffee Intake

AbstractThe increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A2A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chlorogenic acids, also attenuate brain dysfunction, although it is unknown if they control synaptic function. We now used electrophysiological recordings in mouse hippocampal slices to test if realistic concentrations of chlorogenic acids directly affect synaptic transmission and plasticity. 3-(3,4-dihydroxycinnamoyl)quinic acid (CA, 1–10 μM) and 5-O-(trans-3,4-dihydroxycinnamoyl)-D-quinic acid (NCA, 1–10 μM) were devoid of effect on synaptic transmission, paired-pulse facilitation or long-term potentiation (LTP) and long-term depression (LTD) in Schaffer collaterals-CA1 pyramidal synapses. However, CA and NCA increased the recovery of synaptic transmission upon re-oxygenation following 7 min of oxygen/glucose deprivation, an in vitro ischemia model. Also, CA and NCA attenuated the shift of LTD into LTP observed in hippocampal slices from animals with hippocampal-dependent memory deterioration after exposure to β-amyloid 1–42 (2 nmol, icv), in the context of Alzheimer’s disease. These findings show that chlorogenic acids do not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of chlorogenic acids will allow the design of hitherto unrecognized novel neuroprotective strategies.

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