Disruption of Coherent Oscillations in Inhibitory Networks With Anesthetics: Role of GABAA Receptor Desensitization (original) (raw)
Related papers
2015
The effect of anesthetic drugs at central synapses can be described quantitatively by developing kinetic models of ligand-gated ion channels. Experiments have shown that the hypnotic propofol and the sedative benzodiazepine midazolam have similar effects on single inhibitory postsynaptic potentials (IPSPs) but very different effects on slow desensitization that are not revealed by examining single responses. Synchronous oscillatory activity in networks of interneurons connected by inhibitory synapses has been implicated in many hippocampal functions, and differences in the kinetics of the GABAergic response observed with anesthetics can affect this activity. Thus we have examined the effect of propofol and midazolam-enhanced IPSPs using mathematical models of self-inhibited one-and two-cell inhibitory networks. A detailed kinetic model of the GABA A channel incorporating receptor desensitization is used at synapses in our models. The most dramatic effect of propofol is the modulation of slow desensitization. This is only revealed when the network is driven at frequencies that are thought to be relevant to cognitive tasks performed in the hippocampus. The level of desensitization at synapses with propofol is significantly reduced compared to control synapses. In contrast, midazolam increases macroscopic desensitization at network synapses by altering receptor affinity without concurrently modifying desensitization rates. These differences in gating between the two drugs are shown to alter network activity in stereotypically different ways. Specifically, propofol dramatically increases the amount of excitatory drive necessary for synchronized behavior relative to control, which is not the case for midazolam. Moreover, the range of parameters for which synchrony occurs is larger for propofol but smaller for midazolam, relative to control. This is an important first step in linking alterations in channel kinetics with behavioral changes.
Anaesthetic agents such as propofol are known to have an effect on both synaptic and extra-synaptic receptors. On the one hand, binding of propofol to GABA A synaptic receptors induces a phasic inhibition, as opposed to tonic inhibition which seems mainly induced by binding to extra-synaptic receptors. On the second hand, under aneasthesia, an increase in amount of slow oscillations, mainly delta (0-4Hz), concurrent to a decrease of alpha oscillations (8-12Hz), is observed in EEG recordings of occipital areas in most mammals including humans. The latter observation cannot be explained by sole phasic inhibition. Therefore, we propose to investigate, through numer- ical simulations, the role of tonic inhibition in the increase (in amount) of slow oscillations under propofol anaesthesia. To account for the biological realism of our simulations, the cortical model includes two neuronal populations, one excitatory modeled by Type I Leaky integrate-and-fire neurons, one inhibitory modeled...
British Journal of Pharmacology, 1996
General anaesthetic agents prevent awareness of sensory input and subsequent recall of sensory events after administration. The mechanisms involved in higher sensory processing, including awareness and recall, are not fully elucidated. However, fast oscillations in neuronal activity in the 20-80 Hz (gamma) range have been strongly implicated. Here we have investigated the effects of two anaesthetic agents and a sedative/hypnotic drug on these oscillations. 2 Trains of fast oscillations, shown previously to be shaped by y-aminobutyric acid (GABAA) receptor activation, were evoked by pressure ejection of L-glutamate (10 mM) onto the perisomatic region of hippocampal area CAl in the presence of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), 50 4uM, 6-nitro-7-sulphamoylbenzo[flquinoxaline-2,3-dione (NBQX), 50 uM and 2-hydroxysaclofen, 0.2 mM. 3 Thiopentone (10-200 uM) and propofol (0.5-10 uM) dose-dependently decreased both the maximum oscillation frequency, by approx. 90%, and the incidence of evoked rhythmic oscillations by approx. 60%. Diazepam (0.05-1 rM) decreased maximum oscillation frequency by about 40% but did not affect the incidence of evoked oscillations. 4 The similar effects of thiopentone and propofol were mediated by both a large (about 600%) increase in the decay constant (TD) of GABAA receptor-mediated inhibitory postsynaptic currents (i.p.s.cs) and a bicuculline-sensitive leak current. The two drugs had differing effects on i.p.s.c. amplitude. Diazepam caused a small increase in rD (about 170%) and did not alter leak currents at the doses used. 5 Effects of the anaesthetic agents were seen on the above measurements at similar concentrations to those estimated in the CNS during clinical and veterinary anaesthesia. We suggest that the effects on fast oscillations associated with cognition may contribute to the mechanism by which these agents produce general anaesthesia.
British Journal of Pharmacology, 1999
Anaesthetic agents produce disruption in cognitive function typi®ed by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modi®ed by anaesthetic agents. 2 Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30 ± 70 Hz) to beta frequency (12 ± 30 Hz) oscillations. 3 Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma-induced beta oscillation. Thiopental 10 ± 200 mM, Diazepam 0.05 ± 1.0 mM, Morphine 10 ± 200 mM, and Ketamine 10 ± 200 mM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus-induced depolarization respectively. 4 The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma-induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly.
Journal of computational neuroscience, 2014
Anaesthetic agents are known to affect extra-synaptic GABAergic receptors, which induce tonic inhibitory currents. Since these receptors are very sensitive to small concentrations of agents, they are supposed to play an important role in the underlying neural mechanism of general anaesthesia. Moreover anaesthetic agents modulate the encephalographic activity (EEG) of subjects and hence show an effect on neural populations. To understand better the tonic inhibition effect in single neurons on neural populations and hence how it affects the EEG, the work considers single neurons and neural populations in a steady-state and studies numerically and analytically the modulation of their firing rate and nonlinear gain with respect to different levels of tonic inhibition. We consider populations of both type-I (Leaky Integrate-and-Fire model) and type-II (Morris-Lecar model) neurons. To bridge the single neuron description to the population description analytically, a recently proposed stat...
Neuropharmacology, 2015
Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage...
The General Anesthetic Propofol Slows Deactivation and Desensitization of GABAAReceptors
The Journal of Neuroscience
Propofol (2,6-di-isopropylphenol) has multiple actions on GABA A receptor function that act in concert to potentiate GABA-evoked currents. To understand how propofol influences inhibitory IPSCs, we examined the effects of propofol on responses to brief applications of saturating concentrations of GABA (1-30 mM). GABA was applied using a fast perfusion system to nucleated patches excised from hippocampal neurons. In this preparation, propofol (10 M) had no detectable agonist effect but slowed the decay, increased the charge transfer (62%), and enhanced the peak amplitude (8%) of currents induced by brief pulses (3 msec) of GABA. Longer pulses (500 msec) of GABA induced responses that desensitized with fast (f ϭ 1.5-4.5 msec) and slow (s ϭ 1-3 sec) components and, after the removal of GABA, deactivated exponentially (d ϭ 151 msec). Propofol prolonged this deactivation (d ϭ 255 msec) and reduced the development of both fast and slow desensitization. Recovery from fast desensitization, assessed using pairs of brief pulses of GABA, paralleled the time course of deactivation, indicating that fast desensitization traps GABA on the receptor. With repetitive applications of pulses of GABA (0.33 Hz), the charge transfer per pulse declined exponentially (Ϸ 15 sec) to a steady-state value equal to ϳ40% of the initial response. Despite the increased charge transfer per pulse with propofol, the time course of the decline was unchanged. These experimental data were interpreted using computer simulations and a kinetic model that assumed fast and slow desensitization, as well as channel opening developed in parallel from a pre-open state. Our results suggest that propofol stabilizes the doubly liganded pre-open state without affecting the isomerization rate constants to and from the open state. Also, the rate constants for agonist dissociation and entry into the fast and slow desensitization states were reduced by propofol. The recovery rate constant from fast desensitization was slowed, whereas that from slow desensitization appeared to be unchanged. Taken together, the effects of propofol on GABA A receptors enhance channel opening, particularly under conditions that promote desensitization.
Journal of mathematical neuroscience, 2015
With the advances in biochemistry, molecular biology, and neurochemistry there has been impressive progress in understanding the molecular properties of anesthetic agents. However, there has been little focus on how the molecular properties of anesthetic agents lead to the observed macroscopic property that defines the anesthetic state, that is, lack of responsiveness to noxious stimuli. In this paper, we use dynamical system theory to develop a mechanistic mean field model for neural activity to study the abrupt transition from consciousness to unconsciousness as the concentration of the anesthetic agent increases. The proposed synaptic drive firing-rate model predicts the conscious-unconscious transition as the applied anesthetic concentration increases, where excitatory neural activity is characterized by a Poincaré-Andronov-Hopf bifurcation with the awake state transitioning to a stable limit cycle and then subsequently to an asymptotically stable unconscious equilibrium state. ...
General Anaesthetic Modification of Synaptic Facilitation and Long-Term Potentiation in Hippocampus
BJA: British Journal of Anaesthesia, 1989
There is increasing evidence that general anaesthetics may act at multiple membrane sites to depress excitatory transmission in central nervous system pathways, and that the combination of actions which results in anaesthesia may differ among agents [1-5]. This concept represents a significant departure from "unitary" theories of anaesthetic action which propose a common mechanism at a hydrophobic site for all agents [6-8]. The dissimilar molecular structures exhibited by anaesthetics and the variety of possible sites with which anaesthetics can interact in neuronal membranes provide a high probability that molecular sites of action are different for different agents. The present study chose two structurally different inhalation agents, a halogenated hydrocarbon (halothane) and a halogenated ether (methoxyflurane) to test this possibility (fig. 1). Rat hippocampal brain slices were chosen as the test preparation because of the ease of controlled extracellular recording of synaptically evoked responses. We examined anaesthetic actions on the CA1 neurone excitatory postsynaptic potential (EPSP) and population spike (PS), with particular attention to the properties of shortterm synaptic facilitation of the EPSP, pairedpulse potentiation of the PS (PP), and long-term PS potentiation (LTP). Synaptic facilitation, PP and LTP are three common manifestations of use-dependent changes in neuronal excitability. As such, they may be of importance in anaesthesia, but have not been studied systematically in this regard.