Propofol suppresses synaptic responsiveness of somatosensory relay neurons to excitatory input by potentiating GABA(A) receptor chloride channels.
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 microM) 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.
Ying
Shui-Wang
SW
C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, 1300 York Avenue, Room A-1050, New York, NY 10021, USA. svy2001@med.cornell.edu
Goldstein
Peter A
PA
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D018118:Chloride Channels / Q000378:metabolism*; D004357:Drug Synergism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
D018686:Anesthetics, Intravenous; D018118:Chloride Channels; D011963:Receptors, GABA-A; D015742:Propofol