Brotons-Mas, J. R. | Search bioRxiv

bioRxiv2025

Electrophysiological and network dynamics disruption of hippocampal CA1 neurons after NMDAr blockade by MK-801

The N-methyl-D-aspartate receptor (NMDAr) hypofunction hypothesis suggests that excitatory-inhibitory (E-I) imbalance underlies cognitive deficits associated with neuropsychiatric disorders, such as schizophrenia (SCZ). In this study, we investigated the impact of NMDAr blockade on pyramidal neurons and interneurons in the CA1 region of the hippocampus using in vivo electrophysiological recordings during both spontaneous and exploratory behaviors. Through the administration of MK-801, an NMDAr antagonist, we assessed changes in spike train dynamics, network synchrony, and neuronal modulation by oscillatory activity, with particular emphasis on theta, gamma, and sharp-wave ripple (SWR) oscillations. We found that NMDAr blockade significantly disrupted the E-I balance, leading to altered spike train properties, reduced bursting propensity, and impaired neuronal synchronization. These changes were accompanied by decreased modulation of pyramidal neurons and interneurons by theta and gamma oscillations, as well as diminished recruitment of pyramidal neurons during SWR events. Additionally, the correlation between firing rates and movement speed was reduced, reflecting deficits in spatial coding and memory processing. Moreover, MK-801 administration disrupted place cell stability and spatial information processing. These effects likely contribute to functional disconnection between the hippocampus and other brain regions, such as the prefrontal cortex, and may underlie SCZ-associated cognitive impairments. Our findings provide valuable insights into the cellular and network-level mechanisms affected by NMDAr dysfunction, highlighting the role of oscillatory activity and spike timing in cognitive deficits. This work advances our understanding of how NMDAr hypofunction impacts hippocampal circuits and identifies potential targets for therapeutic interventions aimed at restoring cognitive function in neuropsychiatric disorders.

neuroscience↗

bioRxiv2021

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

Abnormal NMDAr function has been linked to rhythmopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). 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), administered the NMDAr antagonist MK801, and recorded 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, impaired spatial working memory, and disrupted the correlation between oscillations and speed of movement, which is crucial for internal representations of distance. In the hippocampus, MK801 increased gamma oscillations and disrupted theta/gamma coupling. In the mPFC, MK801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155-185 Hz), and disrupted theta/gamma coupling. The performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/ low gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might be essential to explaining several of SCZs cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction. Significance StatementNMDAr hypofunction might be the basis of cognitive symptoms and oscillopathies found in SCZ. In this work, we aimed to understand this link further. We found that NMDAr hypofunction altered theta/gamma co-modulation in the hippocampus and the PFC, explaining spatial working memory deficits.

neuroscience↗