Abstract
We present detailed models of pyramidal cells from human neocortex, including models on their excitatory synapses, dendritic spines, dendritic NMDA- and somatic/axonal Na+ spikes that provided new insights into signal processing and computational capabilities of these principal cells. Six human layer 2 and layer 3 pyramidal cells (HL2/L3 PCs) were modeled, integrating detailed anatomical and physiological data from both fresh and postmortem tissues from human temporal cortex. The models predicted particularly large AMPA- and NMDA-conductances per synaptic contact (0.88 and 1.31 nS, respectively) and a steep dependence of the NMDA-conductance on voltage. These estimates were based on intracellular recordings from synaptically-connected HL2/L3 pairs, combined with extra-cellular current injections and use of synaptic blockers, and the assumption of five contacts per synaptic connection. A large dataset of high-resolution reconstructed HL2/L3 dendritic spines provided estimates for the EPSPs at the spine head (12.7 ± 4.6 mV), spine base (9.7 ± 5.0 mV), and soma (0.3 ± 0.1 mV), and for the spine neck resistance (50–80 MΩ). Matching the shape and firing pattern of experimental somatic Na+-spikes provided estimates for the density of the somatic/axonal excitable membrane ion channels, predicting that 134 ± 28 simultaneously activated HL2/L3-HL2/L3 synapses are required for generating (with 50% probability) a somatic Na+ spike. Dendritic NMDA spikes were triggered in the model when 20 ± 10 excitatory spinous synapses were simultaneously activated on individual dendritic branches. The particularly large number of basal dendrites in HL2/L3 PCs and the distinctive cable elongation of their terminals imply that ~25 NMDA-spikes could be generated independently and simultaneously in these cells, as compared to ~14 in L2/3 PCs from the rat somatosensory cortex. These multi-sites non-linear signals, together with the large (~30,000) excitatory synapses/cell, equip human L2/L3 PCs with enhanced computational capabilities. Our study provides the most comprehensive model of any human neuron to-date demonstrating the biophysical and computational distinctiveness of human cortical neurons.
Highlights
Understanding the human brain is of high priority for humankind, as is manifested by the thousands of studies published every year on the various aspects of the human brain and by the large-scale projects initiated in the last decade worldwide (Markram et al, 2015; Amunts et al, 2016; Koch and Jones, 2016; Martin and Chun, 2016; Poo et al, 2016)
Our models show that human L2/L3 PCs have the capacity to generate tens of independent dendritic NMDA spikes
Human Brain Slice Preparation All procedures on human tissue were performed with the approval of the Medical Ethical Committee (METc) of the VU University Medical Centre (VUmc), with written informed consent by patients involved to use brain tissue removed for treatment of their disease for scientific research, and in accordance with Dutch license procedures and the declaration of Helsinki (VUmc METc approval ‘kenmerk 2012/362’)
Summary
Understanding the human brain is of high priority for humankind, as is manifested by the thousands of studies published every year on the various aspects of the human brain and by the large-scale projects initiated in the last decade worldwide (Markram et al, 2015; Amunts et al, 2016; Koch and Jones, 2016; Martin and Chun, 2016; Poo et al, 2016). The resected tissue can be immediately immersed in the fixative and the ultrastructure and quality of the labeling achieved using a variety of markers for histology and immunocytochemistry is comparable to that obtained in experimental animals (del Río and DeFelipe, 1994; AlonsoNanclares et al, 2008). This resected human brain tissue proved to be of great value in the 1980s and 1990s to directly study the functional characteristics of human brain tissue in vitro. There has been renewed interest in using “non-epileptic” cortical samples (removed during surgery on brain tumors) or “nonspiking” regions with normal histology (removed at a distance from the epileptic focus) in epileptic patients, as they provide an unprecedented opportunity to study human cells and local circuits, both biophysically and computationally (Szabadics et al, 2006; Verhoog et al, 2013; Testa-Silva et al, 2014; Tian et al, 2014; Mohan et al, 2015; Varga et al, 2015; Eyal et al, 2016; Molnár et al, 2016)
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