The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the auditory thalamocortical pathway

Abstract

27Efficient sensory processing requires that the brain is able to maximize its 28 response to unexpected stimuli, while suppressing responsivity to expected events. 29Mismatch negativity (MMN) is an auditory event-related potential that occurs when a 30 regular pattern is interrupted by an event that violates the expected properties of the 31 pattern. MMN has been found to be reduced in individuals with schizophrenia in over 32 100 separate studies, an effect believed to be underpinned by glutamate N-methyl-D-33 aspartate receptor (NMDA-R) dysfunction, as it is observed that NMDA-R antagonists 34 also reduce MMN in healthy volunteers. The aim of the current study is to examine this 35 effect in rodents. Using single unit recording in specific auditory areas using methods 36 not readily utilized in humans, we have previously demonstrated that neuronal indices 37 of rodent mismatch responses recorded from thalamic and cortical areas of the brain can 38 be decomposed into a relatively simple repetition suppression and a more sophisticated 39 prediction error process. In the current study, we aimed to test how the NMDA-R 40 antagonist, MK-801, affected both of these processes along the rat auditory 41 thalamocortical pathway. We found that MK-801 had the opposite effect than expected, 42 and enhanced thalamic repetition suppression and cortical prediction error. These single 43 unit data correlate with the recordings of local field responses. Together with previous 44 data, this study suggests that our understanding of the contribution of NMDA-R system 45 to MMN generation is far from complete, and also has potential implications for future 46 research in schizophrenia. 47 48 3 Keywords: Mismatch negativity, predictive coding, prediction error, repetition 49 suppression, schizophrenia, auditory. 50 51 Significance Statement: (120 words -currently 119 words) In this study, we 52 demonstrate that an NMDA-R antagonist, MK-801, differentially affects single neuron 53 responses to auditory stimuli along the thalamocortical axis by increasing the response 54 magnitude of unexpected events in the auditory cortex and intensifying the adaptation 55 of responses to expected events in the thalamus. Thus, we provide evidence that 56 NMDA-R antagonists alter the balance between prediction-error and repetition 57 suppression processes that underlie the generation of mismatch responses in the brain, 58and these effects are differentially expressed at different levels of auditory processing. 59As effects of MK-801 were in the opposite direction to our expectations, it demonstrates 60 that our understanding of role of NMDA-R in synaptic plasticity and the neural 61 processes underpinning MMN generation are far from complete. 62 63 64 65 66 67 68 69 70Mismatch negativity (MMN) is an auditory event-related potential (ERP) that 71 occurs when an unexpected stimulus (deviant, DEV) interrupts a train of regular stimuli 72 (standards, STD) in an oddball sequence. MMN is commonly quantified as the 73 difference between the size of the DEV a...