DuBois-Reymond prize lecture 2024: Multi-neuron patch-clamp to uncover the neuronal and synaptic physiology in the human neocortex.

The physiology of neurons and synapses determines how networks in the brain process information. While these properties are well described in rodents, they are less well established for the human brain. Increasing availability of surgically resected human brain tissue, together with advances in electrophysiology, has enabled new insights into species-specific differences of the human cortical microcircuit. This review highlights recent progress in the physiology of layer 2 and 3 pyramidal neurons of the human temporal cortex, focusing on the multi-neuron patch-clamp approach. Methodological developments such as automated pipette cleaning now allow large-scale mapping of cellular electrophysiology and synaptic connectivity in human cortex. This approach reveals substantial functional heterogeneity among layer 2 and 3 pyramidal neurons with distinct intrinsic properties, morphology, and connectivity patterns. Complex network analyses further uncover human-specific properties, such as a directed network topology with random reciprocity and a decoupling of synaptic strength from connectivity. Network simulations suggest that these wiring patterns expand the computational capacity of cortical microcircuits. Together, these studies showcase the potential of multipatch recordings to bridge rodent and human neurophysiology and to establish an empirical basis for how cellular and synaptic diversity shapes human cortical microcircuits.