Sag currents are a major contributor to human pyramidal cell intrinsic differences across cortical layers and between individuals

Abstract In the human neocortex, coherent theta oscillations between superficial and deep cortical layers are driven by deep layer neurons, suggesting distinct intrinsic electrophysiological properties of neurons across cortical layers. Here, we used in vitro whole-cell recordings to characterize pyramidal cells in layer 2/3 (L2/3) and layer 5 (L5) of the human neocortex. We found that human L5 pyramidal cells were more excitable and were endowed with a more prominent sag voltage and larger Ih currents relative to L2/3 neurons, that were abolished through direct pharmacological blockade. Although no peak in subthreshold resonance was observed for either L2/3 or L5 cells, we found that L5 neurons demonstrated greater spiking gain at low frequencies. Integrating patient-level demographic features revealed larger sag amplitudes in pyramidal cells recorded from older patients. These data suggest that sag is prominently expressed in L5 pyramidal cells and is a dynamic feature of human cortical microcircuits.