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General anaesthetics have been hypothesised to ablate consciousness by decoupling intracortical neural connectivity. We explored this by investigating the effect of etomidate and ketamine on coupling of neural population activity using the low magnesium neocortical slice model. Four extracellular electrodes (50 mu m) were positioned in mouse neocortical slices (400 mu m thick) with varying separation. The effect of etomidate (24 mu M) and ketamine (16 mu M) on the timing of population activity recorded between channels was analysed. No decoupling was observed at the closest electrode separation of 0.2 mm. At 4 mm separation, decoupling was observed in 50% and 42% of slices during etomidate and ketamine delivery, respectively (P less than 0.0001 and P=0.002, compared to 0.2mm separation). A lower rate of decoupling was observed with 1 mm separation (21% and 8%, respectively, P less than 0.03 for etomidate compared to 0.2 mm separation). The data support the hypothesis that mechanistically diverse general anaesthetics disrupt neuronal connectivity across widely distributed intracortical networks.

Clinically, anesthetic drugs show hysteresis in the plasma drug concentrations at induction versus emergence from anesthesia induced unconsciousness. This is assumed to be the result of pharmacokinetic lag between the plasma and brain effect-site and vice versa. However, recent mathematical and experimental studies demonstrate that anesthetic hysteresis might be due in part to lag in the brain physiology, independent of drug transport delay-so-called "neural inertia". The aim of this study was to investigate neural inertia in the reduced neocortical mouse slice model. Seizure-like event (SLE) activity was generated by exposing cortical slices to no-magnesium artificial cerebrospinal fluid (aCSF). Concentration-effect loops were generated by manipulating SLE frequency, using the general anesthetic drug etomidate and by altering the aCSF magnesium concentration. The etomidate (24 mu M) concentration-effect relationship showed a clear hysteresis, consistent with the slow diffusion of etomidate into slice tissue. Manipulation of tissue excitability, using either carbachol (50 mu M) or elevated potassium (5 mM vs 2.5 mM) did not significantly alter the size of etomidate hysteresis loops. Hysteresis in the magnesium concentration-effect relationship was evident, but only when the starting condition was magnesium-containing "normal" aCSF. The in vitro cortical slice manifests pathway-dependent "neural inertia" and may be a valuable model for future investigations into the mechanisms of neural inertia in the cerebral cortex.