Abstract
Propofol is a widely used intravenous general anesthetic. Propofol-induced unconsciousness in humans is associated with inhibition of thalamic activity evoked by somatosensory stimuli. However, the cellular mechanisms underlying the effects of propofol in thalamic circuits are largely unknown. We investigated the influence of propofol on synaptic responsiveness of thalamocortical relay neurons in the ventrobasal complex (VB) to excitatory input in mouse brain slices, using both current- and voltage-clamp recording techniques. Excitatory responses including EPSP temporal summation and action potential firing were evoked in VB neurons by electrical stimulation of corticothalamic fibers or pharmacological activation of glutamate receptors. Propofol (0.6 – 3 μM) suppressed temporal summation and spike firing in a concentration-dependent manner. The thalamocortical suppression was accompanied by a marked decrease in both EPSP amplitude and input resistance, indicating that a shunting mechanism was involved. The propofol-mediated thalamocortical suppression could be blocked by a GABAA receptor antagonist or chloride channel blocker, suggesting that postsynaptic GABAA receptors in VB neurons were involved in the shunting inhibition. GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked in VB neurons by electrical stimulation of the reticular thalamic nucleus. Propofol markedly increased amplitude, decay time, and charge transfer of GABAA IPSCs. The results demonstrated that shunting inhibition of thalamic somatosensory relay neurons by propofol at clinically relevant concentrations is primarily mediated through the potentiation of the GABAA receptor chloride channel-mediated conductance, and such inhibition may contribute to the impaired thalamic responses to sensory stimuli seen during propofol-induced anesthesia.
Highlights
General anesthesia consists of five distinct components: analgesia, amnesia, unconsciousness, immobility, and blunted autonomic responsiveness [1,2]
Propofol suppresses temporal summation in VB neurons The responses of VB neurons in vivo to somatosensory stimuli depend on the state of arousal, and the functional state is linked to neuronal depolarization levels that can be regulated by corticothalamic excitatory (CT) input [8]
Repetitive stimulation (33 Hz, 5 pulses) of the white matter gave rise to incremental excitatory postsynaptic potentials (EPSPs) that showed summation without apparent inhibitory postsynaptic potentials (IPSPs) at membrane potentials of -58 to -54 mV (Fig. 1C), identical to those seen by others [60,63]
Summary
General anesthesia consists of five distinct components: analgesia, amnesia, unconsciousness, immobility, and blunted autonomic responsiveness [1,2]. While the spinal cord is considered to be the anatomic substrate for anesthetic-induced immobility in response to noxious stimulation [3,4], the anatomic foundations for the other components are less well established. Excitatory input regulates the functional state of thalamic neurons, and such input is provided by both ascending activating systems in the brain stem and hypothalamus and the descending (corticothalamic) pathway [8]. During propofol-induced unconsciousness in humans, somatosensory-evoked neuronal activity in the cortex and the thalamus is markedly decreased [24,25]. The cortical suppression may reflect anesthetic actions on projection neurons located elsewhere, especially in the thalamus [22,27]. A significant limitation to the in vivo data from anesthetized animals is the use of "background anesthesia" (typically induced by urethane, sodium pentobarbital or a ketamine/xylazine combination) for baseline recordings; such "background anesthesia" makes it impossible to interpret the data subsequently obtained with the anesthetic(s) of interest [28]
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