Intra-individual Physiomic Landscape of Pyramidal Neurons in the Human Neocortex

Computation within cortical microcircuits is determined by functional properties of the neurons and their synaptic interactions. While heterogeneity of inhibitory interneurons is well established, the anatomical, physiological, and molecular differentiation of excitatory pyramidal neurons is not fully resolved. To identify functional subtypes within the pyramidal neuron population, we focused on human layer 2-3 cortex which greatly expanded during evolution. We performed multi-neuron patch-clamp recordings in brain slices from the temporal cortex of 22 epilepsy patients. We characterized the electrophysiological properties of up to 80 pyramidal neurons per patient, enabling us to assess inter- and intra-individual functional variability. Hierarchical clustering of the high-dimensional parameter space yielded functionally distinct clusters of pyramidal neurons which were present across individuals. This may represent a generic organizational principle converging with previously described transcriptomic heterogeneity. We further observed substantial heterogeneity in physiological parameters with intra-individual variability being severalfold larger than inter-individual variability. The phenotypic variability within and across pyramidal neuron subtypes has important implications for the computational capacity of the cortical microcircuit.