Disruption of Coherent Oscillations in Inhibitory Networks With Anesthetics: Role of GABA_A Receptor Desensitization

Abstract

.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.

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

“…Even slow phases of desensitization have been predicted to influence post-synaptic responses to repeated stimulation (Bianchi and Macdonald, 2002). Drugs that alter desensitization rates of GABARs have been shown to dramatically alter oscillation patterns of inhibitory networks (Baker et al, 2002). Therefore, changes in desensitization kinetics due to changes in subunit composition could have significant functional consequences.…”

Anesthetic-Induced Transitions by Propofol Modeled by Nonlocal Neural Populations Involving Two Neuron Types

“…In this context, experimental studies show that different anesthetic agents differ in their action on excitatory and inhibitory synapses. For instance, the induction agent propofol does not affect the excitatory synapses, but prolongs the decay phase of inhibitory synapses only [9,10]. The present work will examine this effect of propofol.…”

Effects of the anesthetic agent propofol on neural populations

“…Our approach is motivated by the experimental findings on anesthetic agents (Rundshagen et al 2004;Kuizenga et al 2001) with respect to their effect on excitatory and inhibitory synapses. For example, increasing the concentration of the agent propofol prolongs the temporal decay phase of inhibitory GABA A synapses and increases the charge transfer in these synapse (Baker et al 2002) while excitatory synapses remain more or less unaffected (Kitamura et al 2002). In addition, to a good approximation the height of the synaptic response function is maintained for different propofol concentrations (Kitamura et al 2002).…”