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

Abstract

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.