An Integrative Model of Ketamine-Induced Memory Dysfunction: From Synapse to Circuit in Clinical Context Publisher Pubmed



Mohammadi M ; Saeedi A ; Vakilabad A A K ; Seyedi F ; Golkar A ; Baghcheghi Y
Source: NeuroToxicology Published:2026

Abstract

Ketamine presents a modern pharmacological paradox, acting as both a rapid-acting antidepressant and a drug of abuse with significant cognitive consequences. While its therapeutic potential is revolutionary, chronic exposure is increasingly associated with persistent and specific deficits in episodic and working memory. This narrative review moves beyond descriptive lists of ketamine's effects to propose a novel integrative model that delineates the coherent pathophysiological cascade through which chronic ketamine exposure induces memory dysfunction. We synthesize evidence that the initiating event—NMDA receptor antagonism, particularly on GABAergic interneurons—triggers a glutamate surge and glutamatergic dysregulation. This initial insult activates a self-reinforcing and pathological amplifying loop of neuroinflammation (e.g., microglial activation, cytokine release) and oxidative stress (e.g., mitochondrial dysfunction, ROS/RNS generation). These converging insults subsequently suppress BDNF/TrkB neurotrophic signaling and cause synaptic disintegration, impairing the plasticity mechanisms that underlie learning and memory. The cascade structurally culminates in apoptotic neuronal deletion, which permanently degrades the cellular substrate within critical memory circuits. This molecular and cellular pathology ultimately manifests as systems-level dysfunction, specifically the functional disconnection of the hippocampus-prefrontal cortex axis, explaining the core clinical memory deficits. By bridging evidence from synapse to circuit, this integrative model provides a unified framework for understanding individual vulnerability, proposes biomarkers for personalized risk assessment, and identifies targeted neuroprotective strategies to mitigate cognitive harm while preserving ketamine's therapeutic benefits. © 2026 Elsevier B.V.