Subanesthetic ketamine administration decreases deviance detection responses at the cellular, populational and mesoscale connectivity levels
In the neocortex, neuronal processing of sensory events is significantly influenced by context. For instance, responses in sensory cortices are suppressed to repetitive stimuli, a phenomenon termed stimulus-specific adaptation. However, in a context in which that same stimulus is novel, or deviates from expectations, neuronal responses are enhanced. Mismatch negativity (MMN), the electroencephalography waveform reflecting rule violations, is a well-established biomarker for auditory deviant detection. MMN has been shown to depend on intact NMDA receptor signaling across species; nevertheless, the underlying mechanisms are still not completely elucidated at the neural and mesoscale levels. Using multi-electrode array recordings in awake mice, we identified a specific biphasic spiking response in a subpopulation of A1 neurons elicited by deviant, but not standard, sounds, whereby the second peak is abolished by acute subanesthetic injection of ketamine, a partial non-competitive NMDA receptor antagonist. We further showed that the posterior parietal cortex, a critical hub for multisensory integration and sensorimotor coordination, responds to unexpected and deviant, but not repetitive, sounds, and this response is dependent upon intact NMDA receptor-mediated signaling. Finally, to explore the effects of ketamine on inter-cortical communication during deviance detection, we performed Granger Causality and Weighted Phase Lag Index (WPLI) analyses during the presentation of deviant and standard sounds. This analysis showed a unidirectional functional connectivity from A1 to PPC during deviant detection, which is impaired by subanesthetic ketamine administration. By investigating how ketamine modulates neural and inter-regional communication, our findings provide novel insights into the NMDA receptor-dependent mechanisms underlying the processing of novelty and regularity in auditory stimuli.