Isoflurane preferentially modulates synaptic responses to corticocortical stimulation over thalamocortical stimulation

ObjectiveTo test the effect of Isoflurane on synaptic transmission of cortico-cortical and thalamocortical projections to the auditory cortex, and investigate how it modulates cortical sensory information processing to produce unconsciousness. MethodsUsing murine auditory thalamocortical brain slices, afferent pathways from the medial geniculate body (MGB) and layer 1 of the proximal cortex were stimulated to evoke excitatory postsynaptic potentials (eEPSPs) in cortical neurons. Whole-cell recordings were made from pyramidal and fast-spiking neurons in layer 2/3 and layer 5. eEPSPs were evaluated along with intrinsic membrane properties in response to stimulation of both pathways with and without isoflurane. ResultsIsoflurane administration resulted in significant eEPSP amplitude reduction following stimulation of both thalamic and cortical pathways, in layer 2/3 (p=0.015, p<0.001) and layer 5 (p<0.001, p<0.001) pyramidal neurons; while it only significantly reduced eEPSP amplitude in fast-spiking interneurons with cortical stimulation (p<0.001). Overall, isoflurane preferentially suppressed synaptic responses to cortico-cortical stimulation compared to thalamocortical (p=0.0002). Under isoflurane, cortico-cortical compared to thalamocortical stimulation evoked eEPSPs with reduced 10-90% rise time in both layer 2/3 and 5 pyramidal neurons, and shorter latency layer 5 neurons. Paired pulse ratio was not changed by isoflurane application, although an interesting loss of depression trend appear in layer 5 pyramidal neurons stimulated by cortical activation. Additional intrinsic neuronal measurements revealed that isoflurane reduced spike threshold significantly in both layer 2/3 and layer 5 neurons, reduced spike latency in layer 2/3 neurons, and input resistance in layer 5 neurons. However, these intrinsic neuronal changes were not seen in fast-spiking interneurons. All isoflurane induced changes were reversible during wash out. ConclusionsApplication of 1% isoflurane to brain slices significantly reduced the amplitudes of eEPSPs and modulated intrinsic neuronal properties. The effects on eEPSP amplitude were greater for cortical stimulation compared to thalamic stimulation. Isoflurane modulated intrinsic neuronal firing properties in pyramidal neurons, but not in fast-spiking interneurons.