Hyperexcitability of Rat Thalamic and Hippocampal Neurons after Exposure to General Anesthesia During Brain Development
DiGruccio, Michael, Neuroscience - Graduate School of Arts and Sciences, University of Virginia
Todorovic, Slobodan, Department of Anesthesiology, University of Virginia
The prevailing literature proves that common general anesthetics (GAs) cause long-term cognitive changes and neurodegeneration in the developing mammalian brain, especially in the thalamus and hippocampus. However, the possible role of GAs in modifying ion channels that control neuronal excitability has not been taken into consideration. Here in rats exposed to GAs at postnatal day 7, nucleus reticularis thalami (nRT) neurons display a lasting reduction in inhibitory synaptic transmission, an increase in excitatory synaptic transmission, and concomitant alterations of T-type calcium currents (T-currents). Collectively this plasticity of ionic currents leads to increased action potential firing in vitro and increased strength of pharmacologically-induced spike and wave discharges in vivo. Selective blockade of T-currents reversed neuronal hyperexcitability in vitro and in vivo. In the subiculum GA also alters T- current biophysical properties that likely contribute to observed increases in action potential firing. Utilizing another approach to ameliorate GA mediated neuronal function: administration of EUK-134 prior to GA exposure is also shown to attenuate GA mediated hyperexcitability. When considering the development of novel anesthetics, the T-channel antagonist B260 is also shown to preserve thalamocortical neuron function when used as an anesthetic during brain development. In conclusion, drugs that regulate T-channels may improve the safety of GAs used during brain development.
PHD (Doctor of Philosophy)
nucleus reticularis thalami, nRT, T-type calcium channels, general anesthesia, general anesthesia neuro toxicity, isoflurane, sevolfurane, nitrous oxide, midazolam, ventral basal complex, VB, thalamocortical oscillations, tonic action potential, burst action potential
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