The editorial frames the human cortex as a system organized around a delicate balance between three competing demands: information processing, circuit stability, and metabolic efficiency. Human neurons and networks are not optimized for computational power in isolation; they are optimized for capacity, stability, flexibility, and energy efficiency simultaneously. This reframing matters because nearly every major hypothesis about cortical function, from the basis of oscillations to the cellular substrates of epilepsy, has been developed and refined in rodent tissue. If the underlying cellular hardware differs, the conclusions may not transfer. The studies in the collection examine these differences at multiple levels: the morphology and electrophysiology of single neurons, calcium dynamics in dendrites, the balance of excitation and inhibition in microcircuits, the mechanisms of brain oscillations, and the evolutionary changes that shaped specialized human cell types.

One striking example of human specificity comes from a study by Márton and colleagues, who investigated what happens when astrocytic glutamate uptake is blocked in human neocortical tissue. Glutamate is the brain’s principal excitatory neurotransmitter, and astrocytes normally clear it rapidly from the extracellular space. When the researchers blocked glutamate transporters in human tissue, they observed slow inward currents and tonic currents in pyramidal neurons, both mediated by NMDA receptors but not identical in character. Slow inward currents were strongly affected by blocking a specific NMDA receptor subtype, whereas tonic currents showed only partial sensitivity to the same blockade. Intriguingly, these effects diminished with age and were largely absent in tissue from older patients. The findings suggest that ambient glutamate signaling in the human cortex is dynamic and context-dependent, and that it becomes particularly consequential under pathological conditions in which glutamate homeostasis is disrupted, as in epilepsy, stroke, or neurodegenerative disease.

A recurring theme across the collection is the pivotal role of fast-spiking interneurons, or FSINs, in human cortical signaling. These inhibitory cells, which include parvalbumin-expressing basket cells, are crucial for regulating the excitatory-inhibitory balance, for timing and synchronizing oscillatory activity, and for shaping the temporal precision of cortical computations. In the human neocortex, FSINs appear to be uniquely specialized, and several studies converge on their importance. Yoon and colleagues found that when high-frequency electrical stimulation is applied to human cortical tissue, FSINs are preferentially engaged while excitatory neurons are suppressed. Remarkably, FSINs maintain action potential firing even during extended periods of stimulation, while excitatory neurons and other, non-fast-spiking interneurons rapidly become inactive. The stimulation also gradually shifts the balance of synaptic activity within the network, enhancing inhibition. The authors argue that such findings carry direct implications for treating epilepsy and related disorders: stabilizing pathological excitability may involve selectively activating inhibitory microcircuits rather than globally dampening neural activity, a strategy that would be difficult to design without knowing the human-specific response properties of these cells.

Complementary work by Sandle and colleagues added a pharmacological dimension to this picture. They found that activating group I metabotropic glutamate receptors boosts excitatory synaptic transmission predominantly onto FSINs rather than onto other interneuron classes. Similar effects have been reported in rodents, but the underlying mechanisms turned out to be different in human tissue. This dissociation, similar circuit-level outcomes achieved through different cellular pathways, encapsulates what may be the collection’s most important lesson: functional similarity between species does not imply mechanistic conservation. A drug that works in mice by acting on one signaling pathway might act on an entirely different pathway, or fail entirely, in human cortex. For preclinical drug development aimed at psychiatric and neurological disorders, this is more than a technical caveat; it is an argument for testing compounds directly in human tissue before they enter clinical trials.

Szegedi and colleagues deepened the discussion by approaching FSINs from an evolutionary and energetic angle. Fast-spiking interneurons are among the most energy-demanding neurons in the brain, because rapid, high-frequency firing requires substantial ionic flux and continuous ATP consumption. Yet human FSINs exhibit a suite of adaptations that reduce their energy expenditure while preserving fast signaling. These include increased input resistance, a distinct organization of ion channels, simpler dendritic architectures, and specialized synaptic properties. In a cortex that is densely packed and metabolically expensive, minimizing the energetic cost of inhibition may have been a significant pressure in human evolutionary history. The idea that even inhibitory microcircuits were shaped by metabolic economy underscores the editorial’s larger point: the human cortex is a compromise engineered by evolution, not a generic mammalian template enlarged to human proportions.

At the level of individual neurons, several studies revealed how sophisticated human cortical cells are at processing information. Szöts and colleagues examined calcium transients triggered by action potentials in layer 2/3 pyramidal neurons and found impressive spatial complexity along the dendrites. Rather than peaking at the cell body, calcium signals peaked in intermediate dendritic regions, with different dendritic compartments engaging distinct calcium channel types. This paints a picture of dendrites as active computational compartments rather than passive cables relaying signals to the soma. Tore and colleagues expanded on this theme in a review of human-specific neuronal features that may boost information processing. Human pyramidal neurons have lower membrane capacitance, recover faster from synaptic depression, and possess more complex dendritic arrangements than their rodent counterparts. Together, these traits likely enhance the computational bandwidth and flexibility of individual neurons, and they also influence how human neurons respond to neuromodulators and pharmacological compounds, a point that again argues for direct studies in human tissue in translational neuroscience.

At the network level, Yang and Feldmeyer reviewed rhythmic activity in human brain slices and highlighted a central methodological challenge for the field: oscillatory dynamics are profoundly shaped by both biological and methodological factors. Differences in tissue source, slice preparation, recording conditions, and the strategies used to induce network rhythms can substantially alter the frequency, stability, and spatial organization of the resulting oscillations. Rather than treating this variability as a nuisance, the authors suggest it reflects the inherent adaptability of human cortical circuits. Oscillations emerge from the interplay of excitation, inhibition, neuromodulation, and the overall condition of the tissue, and shifts in these dynamics may themselves provide diagnostic insight into neuropsychiatric disorders. This methodological honesty is echoed in the Freiburg framework introduced by Straehle and colleagues, a comprehensive platform that integrates electrophysiology, imaging, molecular analysis, Raman microscopy, and clinical data. Its key strength is the systematic treatment of biological variability among human samples: heterogeneity is viewed not as noise to be averaged away but as a vital source of biological and clinical knowledge.

The collection also situates these findings in evolutionary and developmental context. Libé-Philippot and colleagues emphasize that human neurons arise from extended developmental processes and species-specific molecular changes that shape their excitability, synapse formation, and circuit maturation. Many of these pathways are affected in neurodevelopmental disorders, raising the provocative possibility that the very features underlying human cognitive specialization also confer unique vulnerabilities. Eichler and colleagues focus on synapses in the supragranular cortical layers, a region dramatically expanded in the human brain. Their review highlights the distinctive structural and functional characteristics of human synapses and the plasticity mechanisms that may support long-range integration and complex cortical functions. Across the collection, the supragranular layers repeatedly emerge as a critical site of human specialization, making them a priority target for disease modeling and drug screening.

Taken together, the studies collected in this Research Topic mark a significant conceptual shift in neuroscience: away from viewing the human cortex as a mere extension of animal neuroscience, and toward recognizing it as a system with distinct organizing principles. Excitation must be carefully regulated, inhibition must be fast yet energy-conscious, dendrites must support complex integration, and networks must balance synchrony with adaptability. Rodent models remain invaluable and will continue to anchor the field, but the editorial and its contributors argue that specific synaptic dynamics, interneuron adaptations, and dendritic signaling characteristics found in human tissue cannot be fully understood through animal studies alone. As access to living human tissue improves, analytical techniques mature, and computational methods become more refined, neuroscience is evolving toward a genuinely human-centered understanding of cortical function, one that promises more accurate disease models and more reliable paths from laboratory discovery to effective therapies.

Subject of Research: Use of live human brain tissue to study the unique cellular and circuit properties of the human neocortex for basic research, disease modeling and drug development

Article Title: Editorial: Grey matters in the lab: utilizing human brain tissue for basic research, disease modeling and drug development

Article References: Szegedi, V., Yang, D., Feldmeyer, D., & Lamsa, K. (2026). Editorial: Grey matters in the lab: utilizing human brain tissue for basic research, disease modeling and drug development. Frontiers in Synaptic Neuroscience, 18, Article 1910520. https://doi.org/10.3389/fnsyn.2026.1910520

Image Credits: AI Generated

DOI: 10.3389/fnsyn.2026.1910520

Keywords: human cortex, brain tissue, neurons, synapses, fast-spiking interneurons, NMDA receptors, glutamate, dendrites, brain oscillations, epilepsy, drug development, evolution