Accelerated signal propagation speed in human neocortical microcircuits

Reviewer #1 (Public Review):

The propagation of electrical signals within neuronal circuits is tightly regulated by the physical and molecular properties of neurons. Since neurons vary in size across species, the question arises whether propagation speed also varies to compensate for it. The present article compares numerous speed-related properties in human and rat neurons. They found that the larger size of human neurons seems to be compensated by a faster propagation within dendrites but not the axons of these neurons. The faster dendritic signal propagation was found to arise from wider dendritic diameters and greater conductance load in human neurons. In addition, the article provides a careful characterization of human dendrites and axons, as the field has only recently begun to characterize post-operative human cells. There are only a few studies reporting dendritic properties and these are not all consistent, hence there is the added value of reporting these findings, particularly given that the characterization is condensed in a compartmental model.

Strengths:
The study was performed with great care using standard techniques in slice electrophysiology (pharmacological manipulation with somatic patch-clamp) as well as some challenging ones (axonal and dendritic patch-clamp). Modeling was used to parse out the role of different features in regulating dendritic propagation speed. The finding that propagation speed varies across species is novel as previous studies did not find a large change in membrane time constant or axonal diameters (a significant parameter affecting speed). A number of possible, yet less likely factors were carefully tested (Ih, membrane capacitance). The main features outlined here are well-known to regulate speed in neuronal processes. The modeling was also carefully done to verify that the magnitude of the effects is consistent with the difference in biophysical properties. Hence, the findings appear very solid to me.

Weaknesses:
The role of diameter in regulating propagation speed is well-known in the axon literature.

Reviewer #2 (Public Review):

Summary:
In this paper, Oláh and colleagues introduce new research data on the cellular and biophysical elements involved in transmission within the pyramidal circuits of the human neocortex. They gathered a comprehensive set of patch-clamp recordings from human and rat pyramidal neurons to compare how the temporal aspect of neuronal processing is maintained in the larger human neocortex. A broad range of experimental, theoretical, and computational methods are used, including two-photon guided dual whole-cell recordings, electron microscopy, and computational simulations of reconstructed neurons.

Recordings from synaptically connected pyramidal neurons revealed longer intercellular path lengths within the human neocortex. Further, by using dual whole-cell recordings from soma-dendrite and soma-axon locations, they found that short latencies from soma to soma can be partly attributed to an increased propagation speed for synaptic potentials, but not for the propagation of action potentials along the axon.

Next, in a series of extensive computational modeling studies focusing on the synaptic potentials, the authors observe that the short-latency within large human pyramidal neural circuits may have a passive origin. For a wide array of local synaptic input sites, the authors show that the conductance load of the dendrites, electrically coupled to a large diameter apical dendrite, affects the cable properties. The result is a relatively faster propagation of EPSPs in the human neuron.

The manuscript is well-written and the physiological experiments and biophysical arguments are very well explained. I appreciated the in-depth theoretical steps for the simulations. That passive cable properties of the dendrites are causing a higher velocity in human dendrites is interesting but there is a disconnect between the experimental findings and the model simulations. Based on the present data the contribution of active membrane properties cannot be dismissed and deserves further experiments.

Strengths:
The authors present state-of-the-art 2P-guided dual whole-cell recordings in human neurons. In combination with detailed reconstructions, these approaches represent the next steps in unravelling the information processing in human circuits.

The computational modeling based on cable theory and experimentally constrained simulations provides an excellent integrated view of the passive membrane properties.

Weaknesses:
There are smaller and larger issues with the statistical analyses of the experimental data which muddles the interim conclusions.

That the cable properties alone are the main explanation for speeding the electrical signaling in human pyramidal neurons appears inconsistent with the experimental data.

Some of the electrophysiological experiments require further control experiments to make robust conclusions.

Reviewer #3 (Public Review):

Summary:
This study indicates that connections across human cortical pyramidal cells have identical latencies despite a larger mean dendritic and axonal length between somas in the human cortex. A precise demonstration combining detailed electrophysiology and modeling indicates that this property is due to faster propagation of signals in proximal human dendrites. This faster propagation is itself due to a slightly thicker dendrite, a larger capacitive load, and stronger hyperpolarizing currents. Hence, the biophysical properties of human pyramidal cells are adapted such that they do not compromise information transfer speed.

Strengths:
The manuscript is clear and very detailed. The authors have experimentally verified a large number of aspects that could affect propagation speed and have pinpointed the most important one. This paper provides an excellent comparison of biophysical properties between rat and human pyramidal cells. Thanks to this approach a comprehensive description of the mechanisms underlying the acceleration of propagation in human dendrite is provided.

Weaknesses:
Several aspects having an impact on propagation speed are highlighted (dendritic diameter, ionic channels, capacitive load) and there is no clear ranking of their impact on signal propagation speed. It seems that the capacitive load plays a major role, much more than dendritic diameter for which only a 10% increase is observed across species. Both aspects actually indicate that there is an increase in passive signal propagation speed with bigger cells at least close to the soma. This suggests that bigger cells are mechanically more rapid. An intuitive reason why capacitive load increases speed would also help the reader follow the demonstration.