Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences

Abstract

In the human neocortex coherent interlaminar theta oscillations are driven by deep cortical layers, suggesting neurons in these layers exhibit distinct electrophysiological properties. To characterize this potential distinctiveness, we use in vitro whole-cell recordings from cortical layers 2 and 3 (L2&3), layer 3c (L3c) and layer 5 (L5) of the human cortex. Across all layers we observe notable heterogeneity, indicating human cortical pyramidal neurons are an electrophysiologically diverse population. L5 pyramidal cells are the most excitable of these neurons and exhibit the most prominent sag current (abolished by blockade of the hyperpolarization activated cation current, Ih). While subthreshold resonance is more common in L3c and L5, we rarely observe this resonance at frequencies greater than 2 Hz. However, the frequency dependent gain of L5 neurons reveals they are most adept at tracking both delta and theta frequency inputs, a unique feature that may indirectly be important for the generation of cortical theta oscillations.

Intracellular Properties of Deep-Layer Pyramidal Neurons in Frontal Eye Field of Macaque Monkeys

“…In our recordings, 40% of pyramidal neurons displayed subthreshold resonance at about 2 Hz, with a significant majority present in the low-resistance cluster. This proportion is similar to the one found in a recent study on human cortical pyramidal cells ( Moradi Chameh et al, 2021 ). If such subthreshold resonance is usually associated with the expression of Ih currents ( Beaulieu-Laroche et al, 2018 ; Moradi Chameh et al, 2021 ), we did not find significant correlations between the existence of a large sag voltage and low-frequency resonance when considering all resonant and non-resonant neurons.…”

“…This proportion is similar to the one found in a recent study on human cortical pyramidal cells ( Moradi Chameh et al, 2021 ). If such subthreshold resonance is usually associated with the expression of Ih currents ( Beaulieu-Laroche et al, 2018 ; Moradi Chameh et al, 2021 ), we did not find significant correlations between the existence of a large sag voltage and low-frequency resonance when considering all resonant and non-resonant neurons. This may indicate that additional ionic currents such as the persistent Na + current may also drive the subthreshold resonance observed here.…”

“…More importantly, the origin of our two clusters could emerge from the existence of gradients within L5, determined for instance by soma depth, projection target and/or dendritic complexity. Interestingly, the considerable electrophysiological differences observed within our sample echoes the large variability reported in human neocortical L5 pyramidal cells ( Moradi Chameh et al, 2021 ), that could partially be explained by a gradient in dendritic complexity (with thick or thin-tufted pyramidal cells at the two extremes).…”

Resilience through diversity: Loss of neuronal heterogeneity in epileptogenic human tissue impairs network resilience to sudden changes in synchrony

“…Additionally, we obtained, from patients with mesial temporal sclerosis, recordings from neurons in non-epileptogenic middle temporal gyrus (MTG), which is the overlying cortex routinely removed to approach deep temporal structures. The MTG is a well-characterized part of the human brain, representing a common anatomical region from which non-epileptogenic brain tissue has been studied electrophysiologically and transcriptomically (Hodge et al, 2019; Moradi Chameh et al, 2021; Beaulieu-Laroche et al, 2018; Kalmbach et al, 2021), and thus our primary source of non-epileptogenic neurons. We note that each of these studies classify these neurons as indicative of “seemingly normal” human neurons independent of the patients’ epilepsy or tumor diagnoses (i.e., a best case control given limitations in obtaining human tissue).…”

“…These results precisely align with recent multi-patch data from human cortex (Planert et al, 2021) highlighting that between-individual variability in biophysical properties was smaller than within-individual variability. Therefore the CVs we measure here are more related to within-individual heterogeneity than between-individual heterogeneity, and thus increased CV is in fact more representative of increased intrinsic biophysical heterogeneity (Planert et al, 2021; Moradi Chameh et al, 2021), than between-subject variability.…”