SUB-ANESTHETIC KETAMINE IMPAIRS AUDITORY DEVIANCE DETECTION ACROSS CELLULAR, POPULATION, AND MESOSCALE LEVELS

Detecting unexpected sensory events is crucial for adaptive behavior. In the neocortex, repetitive stimuli elicit reduced responses, whereas deviant stimuli trigger enhanced activity. This phenomenon is reflected in the mismatch negativity (MMN), an EEG biomarker of deviance detection that depends on NMDA receptor function. Despite its importance, the cellular and network mechanisms involved remain poorly understood. We used multi-electrode array recordings in awake mice to investigate how sub-anesthetic ketamine, a partial NMDA receptor antagonist, affects auditory deviance detection. In primary auditory cortex (A1), a subset of neurons exhibited a biphasic spiking response to deviant sounds. The second peak of this response was abolished after ketamine administration, highlighting NMDA receptor-dependent signalling. We also recorded from the posterior parietal cortex (PPC), a key hub for multisensory integration. PPC neurons responded selectively to deviant, but not repetitive, sounds, and this response required intact NMDA receptor function. Functional connectivity analysis using Weighted Phase Lag Index revealed signalling from A1 to PPC during deviant detection. Ketamine disrupted this inter-regional communication, indicating impaired propagation of prediction error signals. Together, these results show that sub-anesthetic ketamine weakens both local neuronal responses and long-range cortical coordination during auditory deviance detection. Our findings, currently under review in the European Journal of Neuroscience, provide new insights into how NMDA receptor hypofunction alters predictive processing in the auditory system. These insights are relevant for interpreting sensory and cognitive deficits in neuropsychiatric disorders and may inform future therapeutic strategies targeting impaired cortical communication.