Neuronal Population Effects of Ketamine on Human Brain Organoids
Arina Nikitina, Christian Bustamante Toro, Raymond Gifford, Carolina M. Camargo, Barbara Mejia-Cupajita, Kenneth S. Kosik
bioRxiv (Cold Spring Harbor Laboratory) March 10, 2026 preprint DOI: 10.64898/2026.03.09.710454 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Human dorsal forebrain organoids (6-month-old) |
| Intervention | Ketamine |
| Dose | 20 μg/mL |
| Topics | Ketamine Esketamine |
| Keywords | Organoid Human brain Forebrain Gene silencing Nerve net Hippocampal formation Connectome Population spike Premovement neuronal activity Long-term potentiation Functional connectivity Multielectrode array Task-positive network |
| Key findings | Ketamine acutely silences human organoid network bursting by disconnecting backbone units, while chronic exposure induces tolerance and reduces network activity and connectivity. |
Abstract
Abstract Ketamine’s rapid neuropsychiatric actions emerge from interactions that span receptors, cells, and circuits, but their net effects on human neuronal population dynamics remain incompletely defined. Here we combine human dorsal forebrain organoids with high-density microelectrode arrays (MEAs) to quantify ketamine’s effects from spikes to networks. In 6-month-old organoids, acute ketamine (20□μg/mL) abolished population bursting while neuronal firing continued mostly unchanged. Spike sorting revealed that mean firing rates declined but not silenced after ketamine Reductions were concentrated within a subset of burst-driver units previously defined as “backbone”. Functional connectivity, estimated with the spike time tiling coefficient (STTC), decreased globally after ketamine. Backbone units displayed elevated connectivity at baseline but were functionally disconnected by ketamine. Graph construction from STTC uncovered widespread network reconfiguration, characterized by redistribution of edges from backbone to non-backbone units leading to loss of hubs and less-interconnected communities. Re-exposure after chronic ketamine treatment no longer silenced population bursting, indicating tolerance. Together, these results show that ketamine acutely silences human organoid networks by disconnecting backbone units, while chronic exposure induces tolerance to re-silencing while reducing the number of backbone units and leaving the network less active and less connected. The organoid-MEA platform provides a scalable, human-relevant system for dissecting circuit-level drug effects.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| S(+)-ketamine Effect on Experimental Pain and Cardiac Output Healthy adult volunteers (10 men and 10 women) | 2009 | Pharmacokinetic-pharmacodynamic modeling study in healthy volunteers | n = 20 |