Differential effects of isoflurane on excitatory and inhibitory synaptic inputs to thalamic neurones in vivo

O. Detsch1, E. Kochs1, M. Siemers2, B. Bromm2 and C. Vahle-Hinz*,2

1 Klinik für Anaesthesiologie, Technische Universität München, München, Germany. 2 Institut für Physiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany*Corresponding author

Accepted for publication: February 22, 2002


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Mechanosensory thalamocortical relay neurones (TCNs) receive glutamatergic excitatory input and are subjected to {gamma}-aminobutyric acid (GABA)Aergic inhibitory input. This study assessed the effects of an increase in concentration of isoflurane on thalamic excitatory and inhibitory mechanisms.

Methods. TCNs (n=15) of the thalamic ventral posteromedial nucleus responding to mechanical stimulation of whiskers were investigated in rats anaesthetized with end-tidal concentrations of isoflurane of ~0.9% (ISOlow, baseline) and ~1.9% (ISOhigh). Response activity induced by controlled vibratory movement of single whiskers was recorded before, during and after iontophoretic administration of the GABAA receptor antagonist bicuculline to the vicinity of the recorded neurone.

Results. The increase in concentration of isoflurane induced a suppression of vibratory responses to 14 (4)% [mean (SEM)] of baseline activity. Blockade of GABAA receptors by bicuculline during ISOlow and ISOhigh caused increases in response activity to 259 (32)% and 116 (25)% of baseline activity, respectively. The increase in isoflurane concentration enhanced overall inhibitory inputs by 102 (38)%, whilst overall excitatory inputs were reduced by 54 (7)%.

Conclusions. These data suggest that doubling the concentration of isoflurane doubles the strength of GABAAergic inhibition and decreases the excitatory drive of TCNs by approximately 50%. The isoflurane-induced enhancement of GABAAergic inhibition led to a blockade of thalamocortical information transfer which was not accomplished by the effects of isoflurane on glutamatergic synaptic transmission alone. Thus, it appears that, with respect to transmission of information in the thalamus, the most prominent action of isoflurane is an enhancement of GABAAergic synaptic inhibition, and that effects on glutamatergic neurotransmission may contribute to a lesser extent.

Br J Anaesth 2002; 89: 294–300

Keywords: anaesthetics, volatile; brain, thalamus; brain, somatosensory system


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Interruption of neurotransmission by volatile anaesthetics may be caused by a suppression of excitatory and/or an enhancement of inhibitory synaptic function, although other mechanisms such as interactions with axonal conduction or intrinsic membrane properties may contribute.15 Numerous in vitro studies have demonstrated that the potentiation of {gamma}-aminobutyric acid (GABA)A receptor-mediated inhibition may be an important mechanism of action for volatile anaesthetics,2 68 but there is also evidence that glutamatergic synaptic transmission may be suppressed.7 912

Thalamocortical relay neurones (TCNs) of the rat somatosensory thalamus were used for this study because their inputs, the neurotransmitters involved, as well as the biological relevance of information conveyed has been investigated extensively.1316 The trigeminal somatosensory pathway transmits tactile information from mechanoreceptors of the face to the cerebral cortex and consists of: the trigeminal nerve, the trigeminothalamic neurones of the brain stem, the TCNs of the ventral posteromedial nucleus (VPM) of the thalamus, and the primary somatosensory cortex.15 Discharges of TCN action potentials in response to stimulation of the receptive field (i.e. the TCN output) is the result of glutamatergic excitatory input (via N-methyl-D-aspartate [NMDA] as well as non-NMDA receptors) and GABAAergic inhibitory input (Fig. 1).1720



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Fig 1 Model and mathematical procedure to analyse the effects of an increase in concentration of isoflurane on excitatory and inhibitory inputs to thalamocortical relay neurones (TCNs) (adapted from 23). The response activity of TCNs was recorded under two levels of isoflurane anaesthesia (ISOlow ~0.9%, ISOhigh ~1.9%) with and without local blockade of GABAA receptors via iontophoretic administration of the GABAA receptor antagonist bicuculline (BIC) to the vicinity of the recorded TCN. This allows quantification of the differential changes in excitatory and inhibitory inputs to the TCN under investigation produced by the increase in concentration of isoflurane. Estimates of {Delta} INHIBITION and {Delta} EXCITATION reflect the changes in the strength of GABAAergic inhibition and glutamatergic excitation (mediated via NMDA and non-NMDA receptors), respectively.

 
The aim of the present study was to quantify the changes in overall excitatory and inhibitory inputs to TCNs induced by an increase in concentration of isoflurane such that transfer of tactile information was suppressed. This situation of thalamic sensory blockade was studied because it has been speculated that this may be one of the mechanisms underlying general anaesthesia.21 22 TCN response activity was recorded before, during and after local GABAA receptor blockade in the presence of low and high concentrations of isoflurane. A similar experimental design has been used previously to delineate the effects of halothane on brainstem respiratory neurones.23 24 A preliminary account of the study has been presented in abstract form.25


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study was performed after approval of the Hamburg University Animal Research Committee on adult Wistar rats using methods reported previously in detail.18 22 26 Anaesthesia was induced by inhalation of isoflurane. No other anaesthetics were used during the study. During surgical preparation, anaesthesia was maintained at 1.5–2.0% end-tidal isoflurane in oxygen. The trachea and femoral vein were cannulated for mechanical ventilation of the lungs and for administration of vecuronium bromide (4 mg kg–1 h–1) for muscle relaxation, respectively. Mean arterial pressure (monitored via a catheter in the femoral artery) was >=80 mm Hg in all rats at all times throughout the study period, without the use of vasopressors. End-tidal carbon dioxide concentration and body temperature were monitored continuously and maintained within normal ranges. End-tidal concentration of isoflurane was monitored continuously; isoflurane concentrations reported here are end-tidal concentrations. The animal’s head was mounted in a stereotaxic holder in the flat-skull position27 and a lateral 3 mm square craniotomy was performed over the right thalamus. At the end of the experiments the animals were killed with pentobarbital.

Neuronal recording, stimulation and iontophoresis
Microelectrode-multibarrel assemblies consisting of a tungsten electrode (2 M{Omega} impedance at 1 kHz) glued alongside a five-barrel micropipette (10–20 µm diameter) were used to simultaneously record extracellular action potentials (spikes) of single neurones and to administer drugs to the vicinity of the recorded neurone by iontophoresis. The electrodes were inserted stereotaxically26 in dorsoventral penetrations and the recording sites in the thalamic VPM nucleus were confirmed by the neurones’ facial receptive fields and their characteristic response features.13 14 18 Following amplification, the neuronal activity was filtered and displayed on an oscilloscope (from which original recordings were photographed) as well as stored on a DAT recorder. Off-line analysis was performed using a window discriminator, an interface, and Spike2 software (Cambridge Electronic Design, UK).

Low-threshold mechanosensory TCNs responding with sustained spike discharges (under baseline anaesthesia) to vibration of whiskers (i.e. the receptive field) were selected.15 Controlled vibratory movement was attained by sinusoidal-shaped stimuli (30–600 Hz; 200–500 µm amplitude; 500 ms duration) applied to single whiskers glued to the probe of a feedback-controlled electromechanical stimulator (Somedic, Sweden). Stimulus parameters were adjusted according to the different sensitivities of the neurones, allowing for optimal and robust sustained responses during baseline conditions (i.e. occurring continuously during the entire duration of the stimulus). Peristimulus time histograms (PSTHs) were generated with a bin width of 1 ms from the neuronal responses to 20 consecutive stimulus repetitions delivered at 2.5 s intervals. From these PSTHs, neuronal activities were determined as mean discharge frequencies (spikes s–1): ongoing activity was measured from the 1 s period preceding stimulus onset, and response activity (per stimulus) was determined from the discharge rate present during stimulus application (corrected for the underlying ongoing activity).

The barrels of the micropipette were filled with the competitive GABAA receptor antagonist bicuculline methochloride (5–10 mM in 165 mM NaCl, pH 3.0), the GABAA receptor/chloride channel blocker picrotoxin (5 mM in 165 mM NaCl, pH 3.5), GABA (0.5 M in distilled water, pH 3.5), and 0.9% NaCl. Drugs were ejected with positive currents, and negative currents were applied at all times outside periods of drug ejection (to prevent leakage of the drugs) using an iontophoresis device with a current balancing unit (NPI Electronic, Germany). GABAA receptor antagonists were ejected with incremental currents to achieve an optimal drug effect (i.e. a maximally obtainable increase in response activity without affecting ongoing activity or spike integrity). This approach is important because excessive doses of these drugs may induce ‘spontaneous’ activity or high-frequency discharges, leading to spike decrement and failure by enrollment of non-synaptic mechanisms.28 In addition, doses of GABAA antagonists were tested under baseline anaesthesia against iontophoretic administration of GABA and only doses that antagonized the GABA-induced suppression of response activity were used. In this way, it was possible to obtain an estimate of the effective microiontophoretic ‘dose’ (derived from the product of the intensity of the ejecting current and the duration of ejection) at which the antagonist could be used to ensure a receptor-selective effect. Currents of 40–140 nA applied for 2–15 min were used for bicuculline and picrotoxin administration. Also, the tests with picrotoxin showed similar results as bicuculline administration; thus, potential effects of bicuculline on potassium channels28 29 were unlikely. Data were sampled during periods of reproducible, unchanged drug effects.

Experimental protocol
The experimental sequence consisted of recordings of neuronal activities before (control), during and after (recovery) iontophoresis of drugs under a low concentration of isoflurane (ISOlow) and after approximately doubling the concentration of isoflurane (ISOhigh). Following recordings under ISOhigh, neuronal activities were reassessed after return to baseline. After each change in concentration of isoflurane, an equilibration period of at least 20 min was allowed before data acquisition. Iontophoresis of drugs was followed by full recovery of response activity.

Baseline concentrations of isoflurane of 0.8–1.0% (ISOlow: mean concentration 0.9%) were used to take into account the individual rat’s susceptibility to isoflurane. Adequacy of baseline anaesthesia was based on the absence of haemodynamic reactions to noxious stimuli. The concentration of isoflurane was increased to 1.6–2.2% (ISOhigh: mean concentration 1.9%), aiming to almost completely suppress the response, with stimuli eliciting only a few response spikes (see Fig. 2A). This procedure allowed production of a clear effect of isoflurane while the spike under investigation could still be identified. The concentration of isoflurane was adapted according to its variant effects on neuronal activity in different rats.



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Fig 2 Effects of isoflurane and blockade of local GABAA receptors on response activity of a single thalamocortical relay neurone (TCN). (A) Under ISOlow, 34 Hz vibration of a whisker (bottom trace) elicited spike discharges occurring phase locked to the cycles of the stimuli. Administration of the GABAA receptor antagonist bicuculline (BIC) caused an increase in response activity (see also B). The responses were essentially abolished by the increase in concentration of isoflurane (ISOhigh). Responses were re-established under ISOhigh with bicuculline iontophoresis. The initial response activity reappeared after return to ISOlow. Recovery records sampled after each drug administration are not shown. Each peristimulus time histogram is a count of action potential discharges into successive 1 ms bins, accumulated over 20 consecutive stimulus presentations. Insets show oscilloscope traces of single responses under ISOlow and ISOhigh. (B) Quantification of the effects of an increase in concentration of isoflurane on excitatory and inhibitory inputs to the TCN. The inhibitory constants {alpha}1 and {alpha}2, {Delta} INHIBITION and {Delta} EXCITATION were calculated using the response activities before and during bicuculline administration under ISOlow and ISOhigh (top) according to the equations given in Figure 1. In this neurone, the increase in concentration of isoflurane caused an enhancement of inhibitory inputs by 75% and a reduction of excitatory inputs by 29%, which concomitantly led to a reduction of the response activity by 99% (bottom).

 
Data and statistical analysis
The model for data analysis used in the present study was introduced by Stuth and colleagues. 23 24 The mathematical procedures are outlined in Figure 1 and the underlying assumptions are discussed later. Briefly, the model assumes that the response activity of the TCN (i.e. its output) is the product of its excitatory input (via both types of ionotropic glutamate receptor) and a modulation coefficient (1–{alpha}), where the inhibitory constant {alpha} describes the strength of inhibitory input (via GABAA receptors). During maximal local blockade of GABAA receptors by administration of bicuculline, the neurone’s output equals its excitatory input (since its inhibitory input is completely blocked), and {alpha} becomes zero. Recording TCN response activity before and during blockade of GABAA receptors under ISOlow and ISOhigh allows calculation of estimates for the effects of the increase in concentration of isoflurane on overall excitatory ({Delta} EXCITATION) and inhibitory inputs ({Delta} INHIBITION) to TCN. Inhibitory constants were determined for the low ({alpha}1) and the high ({alpha}2) concentration of isoflurane. (F[ISOlow+bicuculline]) and (F[ISOlow]) are the response activities (in spikes s–1) during blockade of GABAA receptors and during the control period, respectively, both under ISOlow. (F[ISOhigh+bicuculline]) and (F[ISOhigh]) are the respective response activities under ISOhigh. Data are given as mean (SEM). Wilcoxon tests were used for statistical analyses, and P<0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Quantitative data were obtained from 15 TCNs activated with vibratory stimulation of single whiskers under a low concentration of isoflurane of ~0.9% (ISOlow) and a high concentration of ~1.9% (ISOhigh). Discharge activity of a typical TCN during control periods and during blockade of GABAA receptors by bicuculline under ISOlow and ISOhigh is shown in Figure 2. Original spike records demonstrate a single response to the 34 Hz vibration of a whisker under ISOlow and ISOhigh, respectively (Fig. 2A, insets), while the PSTHs depict 20 consecutive responses to repeated stimulus presentations. Under ISOlow, administration of bicuculline significantly increased the response activity while the phase-locked occurrence of response discharges remained unchanged. The increase in concentration of isoflurane caused an almost complete suppression of response activity, which could be re-established by bicuculline administration.

Quantitative analysis (Fig. 2B top) shows that the control baseline response activity (F[ISOlow]) amounted to 15.5 spikes s–1 and increased during bicuculline administration (F[ISOlow+bicuculline]) to 35.8 spikes s–1. The inhibitory constant {alpha}1 of 0.57 [(35.8–15.5)/35.8=0.57] indicates that, under ISOlow, neuronal activity is attenuated via GABAAergic inhibition by 57%, resulting in a neuronal output of 43% of the excitatory input [output=(1–{alpha}) x excitatory input: (1–0.57) x 35.8 spikes s–1=15.5 spikes s–1 (i.e. control response activity)]. Under ISOhigh, neuronal activity is attenuated by 99% ({alpha}2=0.99). The term {Delta} INHIBITION is calculated as 0.75[({alpha}2{alpha}1)/{alpha}1: (0.99–0.57)/0.57=0.75], indicating that the increase in concentration of isoflurane enhanced GABAAergic inhibition by 75%. Using the values for the response activities during bicuculline administration under ISOlow (35.8 spikes s–1) and ISOhigh (25.4 spikes s–1), the term {Delta} EXCITATION is calculated as –0.29 [(25.4–35.8)/35.8=–0.29], indicating that the increase in concentration of isoflurane caused a suppression of the neurone’s excitatory input by 29% (Fig. 2B bottom).

Figure 3 shows the population data for all 15 TCNs studied. The increase in concentration of isoflurane caused a suppression of the responses of TCNs, reflected by a decrease in response activity from 32.3 (5.0) spikes s–1 (ISOlow) to 3.3 (0.7) spikes s–1 (ISOhigh) (P<0.001). Administration of bicuculline significantly enhanced response activities under both isoflurane doses [74.6 (11.2) and 29.4 (4.7) spikes s–1, respectively; P<0.001). Recovery data demonstrate the stability of the preparation over time (Fig. 3A). Pooled data analysis (Fig. 3B) revealed values for {Delta} INHIBITION of 1.02 (0.38) and for {Delta} EXCITATION of –0.54 (0.07). These data indicate that the increase in concentration of isoflurane caused a suppression of response activity by 86 (4)% and this resulted from a concomitant mean enhancement of inhibitory mechanisms by 102% and a mean suppression of excitatory mechanisms by 54%.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The major finding of the present study using an acute rat preparation with intact pathways is that an increase in isoflurane concentration from ~0.9% to ~1.9%, which results in a suppression of thalamic tactile responses, doubles the strength of GABAAergic inhibitory input to and decreases excitatory drive of TCNs by approximately 50%. A strictly ‘mathematical’ interpretation of these data suggests that doubling the inhibitory input might result in the same effect on TCN response activity as halving the excitatory input; however, this was not the case because isoflurane-induced enhancement of GABAAergic inhibition led to a block of thalamocortical information transfer, which was not accomplished by the effect of isoflurane on glutamatergic synaptic transmission alone. Therefore, our data suggest that, with respect to transmission of information in the thalamus, enhancement of GABAAergic synaptic inhibition may be a major mechanism of action of isoflurane, and that suppression of excitatory inputs may contribute to a lesser extent. In addition, the latter effect may reflect the composite effect of isoflurane on subthalamic and corticothalamic neuronal circuits which use glutamate and/or GABA as transmitters. It should be noted that our findings are based on assumptions underlying the method of analysis used, which are discussed below.

Isoflurane-induced suppression of TCN response activity represents a thalamic block of information transfer regarding tactile events affecting the body surface, and this results in a functional deafferentation of the cortex. These data are in keeping with a functional magnetic resonance imaging study which showed that isoflurane impairs thalamocortical transmission of sensory signals in humans.30 The thalamic block of sensory signals may contribute to the state of anaesthesia, a view already put forward by Angel.21 This is further supported by a positron emission tomography study in humans suggesting that the isoflurane-induced suppression of thalamocortical output may underlie the loss of consciousness associated with the anaesthetic state.31 In the present study, the block of information transfer was reversed by antagonism of thalamic GABAA receptors, which is in agreement with a previous study.26 Considering the biological relevance of information processing, this underlines our notion that the effects of isoflurane on TCN inhibitory inputs are more important than the effects on excitatory inputs, since antagonism of GABAA receptors under ISOhigh restored thalamocortical information transfer despite prevailing suppression of excitatory inputs by 54%.

The increase in concentration of isoflurane caused roughly a halving of excitatory TCN input. This should be compared with an attenuation by ~40% of the ascending afferent TCN input induced by an increase in concentration of isoflurane equivalent to the present study.22 In the previous study, TCN input was quantified using recordings from trigeminothalamic neurones, which constitute neurones immediately presynaptic to TCNs. Therefore, the slightly larger reduction of the excitatory TCN input demonstrated in the present study may involve effects additional to those on the ascending afferent input to TCNs. In our in vivo preparation the term {Delta} EXCITATION represents a composite estimate for the change in overall excitatory TCN input. First, it reflects the effects of isoflurane on the entire ascending subthalamic pathway of the somatosensory system, which consists of two glutamatergic synapses (one in the brain stem and one in the thalamus) and the associated modulatory networks involving GABAergic inhibition.15 Secondly, {Delta} EXCITATION represents an additonal excitatory input to TCNs which derives from descending corticothalamic projections. These projections exert facilitatory effects on thalamic response transmission,32 which may also be affected by direct and/or indirect actions of isoflurane on glutamatergic and/or GABAergic neurotransmission at the cortical level.

Our data are at variance with those of Stuth and colleagues,23 24 who introduced the experimental protocol for the quantification of neuronal inputs used here. Using a dog preparation with intact pathways, a similar reduction was noted of both the excitatory glutamatergic and inhibitory GABAAergic transmission to medullary expiratory neurones following a stepwise increase of halothane concentration from 0.9% to 1.8%.23 The authors concluded that the effect of the increase in halothane concentration was caused by a reduction of excitatory mechanisms and not by an enhancement of inhibitory mechanisms. In a subsequent study using a decerebrate dog preparation, the effects of 0.9% halothane were compared with a drug-free baseline.24 Here, the authors showed that halothane per se caused a reduction in excitatory input and an enhancement of inhibitory input. Differences in experimental models and neuronal networks involved and/or the anaesthetics studied may be reasons inter alia for the partly discrepant findings with our results. It is unknown to what degree interactions of isoflurane with intrinsic membrane properties (e.g. via actions on potassium channels)35 and/or other putative neuronal targets may have contributed to our findings. However, the importance of these actions, which have only been demonstrated in in vitro studies thus far, is still under debate.2 Our results are in line with a recent study showing that isoflurane produces its greatest effects on GABAergic synapses, with only small effects on glutamatergic synapses.7

Model assumptions and methodological considerations
The first assumption for an appropriate quantification of neuronal inputs is that TCN response activity is mainly driven by afferent excitatory and GABAAergic inhibitory inputs. It has been demonstrated that the response activity of TCNs in the rat VPM is mainly dependent on excitatory inputs via NMDA and non-NMDA receptors17 20 and that this afferent synaptic transmission is characterized by a high safety factor,18 33 indicating that information regarding tactile stimuli transmitted by brain stem neurones reaches TCNs largely unchanged. The output of TCNs is, however, shaped by GABAAergic inhibitory mechanisms18 19 originating almost exclusively in GABAAergic projections from the thalamic reticular nucleus, since the somatosensory thalamus of the rat is virtually devoid of inhibitory interneurones.14 15

Another assumption for the model is that the GABAAergic inhibitory mechanism operates in a multiplicative fashion. This concept of multiplication of excitatory and inhibitory inputs was first introduced by McCrimmon and colleagues34 for brainstem respiratory neurones. A similar tonically active GABAAergic mechanism governs the output of mechanosensory TCNs of the rat VPM;18 19 as Figure 2A exemplifies, bicuculline administration under ISOlow caused an amplification of the TCN response pattern which was a proportional replica of the initial response pattern. The finding that the response activity during blockade of GABAA receptors under ISOlow and ISOhigh is linearly related to control activity (P<0.02; factor 1.6 and 2.6, respectively) supports this concept.

The degree of GABAA receptor blockade will influence the accuracy of the quantification of changes in neuronal inputs. We are confident that our experimental protocol for drug administration caused a complete blockade of GABAA receptor-mediated inhibition since: (i) iontophoretically administered GABA was antagonized by the bicuculline doses used; and (ii) excessive doses of bicuculline were avoided because these may cause direct excitation of neurones in addition to the actions of bicuculline at GABAA receptors and may, for example, result in the appearance of ‘spontaneous’ activity.28 35

As a result of the absence of a drug-free baseline (an inherent shortcoming of our acute rat preparation with intact pathways) we were not able to study the effects of isoflurane anaesthesia per se; instead, we studied the effects of an increase in concentration of isoflurane. This increase, however, produced a clear change in TCN function from transfer of information regarding sensory stimulation to its block. Influences of changes of haemodynamics on neuronal activity are considered to be negligible because decreases in arterial pressure exceeding those of the present study were shown not to affect TCN discharge activity.22



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Fig 3 (A) Population data (n=15; mean and SEM) depicting the isoflurane-induced suppression of response activity (*P<0.001 vs baseline), and the enhanced response activities induced by blockade of local GABAA receptors (+bicuculline) under both the low and the high concentration of isoflurane (**P<0.001 vs respective control; {dagger}P<0.001 vs +bicuculline at ISOlow). (B) The increase in concentration of isoflurane caused an enhancement of inhibition of TCNs (reflected by a mean change in inhibition of 102%), whilst the excitatory input to TCNs was suppressed (reflected by a mean change of excitation of –54%). Both effects contributed to the resulting net suppression of TCN response activity of 86 (4)%.

 

    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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