General Anesthesia Decouples Cortical Pyramidal Neurons
Authors: Mototaka Suzuki
Matthew E Larkum
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: acetylcholine; anesthesia; consciousness; cortex; dendrites
Affiliations: NeuroCure Cluster of Excellence, Institute for Biology, Humboldt University of Berlin, Chariteplatz 1, 10117 Berlin, Germany. Electronic address: ., NeuroCure Cluster of Excellence, Institute for Biology, Humboldt University of Berlin, Chariteplatz 1, 10117 Berlin, Germany.

Abstract:  The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity. 

Retracted: No

PubPeer comments:
 This paper offers yet another theory of general anaesthesia. Anaesthetic molecules have been shown to affect many, many molecules and processes. What is missing here, as always, is the gain-of-function experiment employing the suggested mechanism. Yes it s hard to do, but until then, this is just another theory. The similar effects of three different general anaesthetics are a poor substitute for the gain-of-function experiment, because correlations between anaesthetic molecules have been observed in many potential mechanisms. There is a typical example in this review by Franks: Franks (2009) Molecular targets underlying general anaesthesia https: doi.org 10.1038 sj.bjp.0706441  (I note in passing that there is a HILARIOUS table at the bottom of the relevant wikipedia page extolling the virtues of the loony quantum microtubule hypothesis: https: en.wikipedia.org wiki Theories_of_general_anaesthetic_action#Microtubule_quantum_vibration_theory_of_anesthetic_action ) Finally, the present paper suffers from small (sometimes very small) samples and some rather loose statistical inference, such as deducing from p 0.05 that no effect is present. E.g. on p669  ... however, they did not impair the fast somatic component (all p 0.05, Wilcoxon rank-sum test, n = 3 mice for both APV and nifedipine; Figure 4B). E.g. on p671  ACh blockers significantly reduced the wakefulness-enhanced somatic responses (all p 0.005, two-sided Wilcoxon rank-sum test, n = 4 mice; Figures 5B and 5D) whereas NA blockers did not (all p 0.05, two-sided Wilcoxon rank-sum test, n = 4...) ,