Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms.

TitleIsoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms.
Publication TypeJournal Article
Year of Publication2009
AuthorsYing S-W, Werner DF, Homanics GE, Harrison NL, Goldstein PA
Date Published2009 Feb
Keywords4-Aminopyridine, Action Potentials, Alanine, Anesthetics, Inhalation, Animals, Biophysics, Dose-Response Relationship, Drug, GABA Agonists, gamma-Aminobutyric Acid, Histidine, Inhibitory Postsynaptic Potentials, Isoflurane, Leucine, Mice, Mice, Transgenic, Mutation, Neural Inhibition, Neurons, Patch-Clamp Techniques, Potassium Channel Blockers, Pyridazines, Receptors, GABA-A, Serine, Thalamus, Time Factors

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) alpha1 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 (1/2) 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 alpha1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate alpha1 subunit-containing GABA(A)-Rs into synapses. In RTN neurons, which lack the alpha1 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 Ba(2+)-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.

Alternate JournalNeuropharmacology
PubMed ID18948126
PubMed Central IDPMC2668243
Grant ListR01 GM066840-05 / GM / NIGMS NIH HHS / United States