Isoflurane modulates excitability in the mouse thalamus via

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• 作者：Shui-Wang Ying ; David F. Werner ; Gregg E. Homanics ; Neil L. Harrison ; Peter A. Goldstein
• 关键词：Volatile anesthetic ; GABA_A receptor ; Potassium channel ; Reticular thalamic nucleus (RTN) ; ventrobasal (VB) thalamus
• 刊名：Neuropharmacology
• 出版年：2009
• 出版时间：February 2009
• 年：2009
• 卷：56
• 期：2
• 页码：438-447
• 全文大小：666 K

文摘

GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA_A receptor (GABA_A-R) α1 subunit; this mutation abolished sensitivity to the volatile anesthetic isoflurane in recombinant GABA_A-Rs, and reduced in vivo sensitivity to isoflurane in the loss-of-righting-reflex assay. We examined the effects of the double mutation on GABA_A-R-mediated synaptic currents and isoflurane sensitivity by recording from thalamic neurons in brain slices. The double mutation accelerated the decay, and decreased the ½ width of, evoked inhibitory postsynaptic currents (eIPSCs) in VB neurons and attenuated isoflurane-induced prolongation of the eIPSC. The hypnotic zolpidem, a selective modulator of GABA_A-Rs containing the α1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate α1 subunit-containing GABA_A-Rs into synapses. In RTN neurons, which lack the α1 subunit, eIPSC duration was longer than in VB, regardless of genotype. Isoflurane reduced the efficacy of GABAergic transmission from RTN to VB, independent of genotype, suggesting a presynaptic action in RTN neurons. Consistent with this observation, isoflurane inhibited both tonic action potential and rebound burst firing in the presence of GABA_A-R blockade. The suppressed excitability in RTN neurons is likely mediated by isoflurane-enhanced Ba²⁺-sensitive, but 4-aminopyridine-insenstive, potassium conductances. We conclude that isoflurane enhances inhibition of thalamic neurons in VB via GABA_A-R-dependent, but in RTN via GABA_A-R-independent, mechanisms.