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

Planert H*, Mittermaier FX*, Grosser S*, Fidzinski P, Schneider UC, Radbruch H, Onken J, Holtkamp M, Schmitz D, Alle H, Vida I, Geiger JRP, Peng Y.

*equal contribution

 

Nat Neurosci. 2026 Feb; 29(2): 455-466.
doi: 10.1038/s41593-025-02134-7. Epub 2025 Dec 10. PMID: 41372679; PMCID: PMC12880919.
Download summary: ReTune PoM 2026 Feb

Understanding how large-scale brain signals emerge from underlying cellular activity remains a central challenge when translating neuron level mechanisms into thera­peutic strategies. While human recordings in patients, such as LFP, ECoG or MEG, provide powerful access to network-level dynamics, the cellular and microcircuit mechanisms that ge­nerate these signals are still poorly understood. In this con­text, the present study by Planert et al. provides a fundamental contribution by resolving the functional diversity and synaptic connectivity principles in human cortical neurons.

Using high-throughput multineuron patch-clamp recordings in human temporal cortex, the authors characterized more than 1,400 neurons and over 1,400 synaptic connections. They iden­tify four distinct electrophysiological subtypes of layer 2–3 pyramidal neurons, each defined by specific intrinsic proper­ties, morphology, and connectivity patterns. Crucially, these subtypes form structured synaptic subnetworks with subtype-specific connectivity. This work demonstrates that pyramidal neurons in the human cortex are not homogeneous but are composed of functionally specialized neuron subtypes that dif­ferentially integrate and communicate information. For exam­ple, some subtypes preferentially receive many inputs and may act as integrators, whereas others form sparse but strong and short-term depressing synapses, suggesting roles in selective signal propagation. At the same time, synaptic properties ex­hibit substantial variability, indicating a rich parameter space for flexible computation within a structured framework. In a separate study on the same dataset, the authors have also identified directed and acyclic network properties of this net­work which can support more complex network computations (Peng et al., Science 2024). These studies show that neuronal diversity and structured connectivity directly translate into dis­tinct computational properties within human cortical circuits.

From a ReTune perspective, this study provides a critical bridge across scales. The diversity of cellular subtypes and their synaptic interactions form the mechanistic substrate from which mesoscopic signals such as LFPs and macro­scopic signals such as EEG or ECoG emerge. Understanding these cellular and synaptic principles is essential for inter­preting patient recordings and for linking observed oscilla­tory patterns, such as beta or gamma activity, to underlying circuit mechanisms. Ultimately, this work lays a foundation for mechanistic models of cortical computation in humans. By revealing how specific neuron types contribute to circuit dynamics, it advances our ability to translate between cellu­lar physiology and the network-level signals that could guide future brain-computer-interfaces and neuromodulation thera­pies such as deep brain stimulation.

 

Dr. Henrike Planert & Franz Mittermaier.

They are two co-first authors of the study and use the multi-patch approach to study principles of synaptic physiology in human brain slices. Henrike Planert is a postdoctoral researcher, and Franz Mittermaier is a medical doctorate can­didate with neurosurgical training, both at the Institute of Neurophysiology at the Charité.

Dr. Yangfan Peng & Prof. Jörg Geiger

Peng & Geiger have co-led this study at the Institute of Neurophysiology, Cha­rité Berlin. Geiger is the director of the Institute of Neurophysiology. Peng is a Emmy Noether group leader within the Movement Disorders and Neuromodu­lation Unit and the Institute of Cell and Neurobiology at Charité. He focus is on translating principles of cortical micro­circuits across species and link those to in vivo population dynamics recorded using high-density electrodes

 

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