NMDAr BLOCKING BY MK801 ALTERS HIPPOCAMPAL AND PREFRONTAL CORTEX OSCILLATIONS AND IMPAIRS SPATIAL WORKING MEMORY IN MICE

Abstract

AbstractAbnormal NMDAr function has been linked to rhythmopathies, psychosis, and cognitive dysfunction in schizophrenia. Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal hippocampus and medial prefrontal cortex (mPFC) and administered them with the NMDAr antagonist MK801, recording oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade increased locomotor activity and impaired spatial working memory. The administration of MK801 disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK801 impaired gamma oscillations and theta/gamma coupling, while in the mPFC, it increased the power of theta, gamma, and generated high-frequency oscillations (HFO 155-185 Hz). Spatial working memory tests in the y-maze revealed that theta/gamma coupling was consistently higher in correct trials. Theta/gamma co-modulation mediated by NMDAr function might be key to explain various of schizophrenia’s cognitive symptoms. Further investigating NMDAr hypofunction’s role in the emergence of aberrant oscillatory activity will improve our understanding of schizophrenia and inspire new treatments of psychiatric disorders.Highlights–NMDAr blockade increases motor behavior and impairs spatial working memory.–NMDAr hypofunction differentially alters oscillatory activity in the hippocampus and PFC.–NMDAr blockade generates locally modulated high-frequency oscillations in the PFC.–Theta/gamma modulation, but also long-range theta/gamma modulation across CA1 and the PFC is involved in spatial working memory.–NMDAr blockade disrupts the correlation between theta/gamma co-modulation and spatial working memory performances.