Electrophysiological classification of human layer 2–3 pyramidal neurons reveals subtype-specific synaptic interactions

Henrike Planert, Franz Xaver Mittermaier, Sabine Grosser, Pawel Fidzinski, Ulf Christoph Schneider, Helena Radbruch, Julia Onken, Martin Holtkamp, Dietmar Schmitz, Henrik Alle, Imre Vida, Jörg Rolf Paul Geiger, Yangfan Peng

Nature Neuroscience12/10/2025·DOI·Read paper

Abstract

Abstract Understanding the functional principles of the human brain requires deep insight into its neuronal and network physiology. In superficial layers of temporal cortex, molecular and morphological subtypes of glutamatergic excitatory pyramidal neurons have been described, but subtyping based on electrophysiological parameters has not been performed. The extent to which pyramidal neuron subtypes contribute to the specialization of physiological interactions by forming synaptic subnetworks remains unclear. Here we performed whole-cell patch-clamp recordings of more than 1,400 layer 2–3 (L2–3) pyramidal neurons and 1,400 identified monosynaptic connections in acute slices of human temporal cortex. We extract principles of neuronal and synaptic physiology along with anatomy and functional synaptic connectivity. We also show robust classification of pyramidal neurons into four electrophysiological subtypes, corroborated by differences in morphology and decipher subtype-specific synaptic interactions. Principles of microcircuit organization are found to be conserved at the individual level. Such a fine network structure suggests that the functional diversity of pyramidal neurons translates into differential computations within the L2–3 microcircuit of the human cortex.

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