Neurophysiological Effects of NMDA Receptor Antagonism in Adolescence vs. Adulthood: EEG as a Translational Tool to Study Schizophrenia

Abstract

Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. The first goal of this study was to develop a tool to record skull EEG in awake behaving rats in a similar manner to how human EEG are obtained. Using this novel rodent EEG technique, I tested whether acute NMDA receptor (NMDAR) antagonism replicates the effects of acute NMDAR-antagonism in humans, and found a strikingly similar shift in EEG oscillatory power from low to high frequencies in rodents, mimicking the effects reported in humans. After validating the translational potential of this approach, I paired EEG with local field recordings to investigate if a disruption to NMDAR signaling during a critical period of development caused long-lasting alterations in neural oscillations in adulthood. I found that rats exposed to an NMDAR-antagonist during adolescence, a critical period for the development of local and long-range synchrony in the brain, showed decreased gamma (30-50 Hz) synchrony between the medial prefrontal cortex (mPFC) and ventral hippocampus (HP) that was evident after NMDAR-antagonist re-exposure during adulthood. The same treatment given to adult rats did not produce this disruption to long-range synchrony, suggesting that adolescent disruption of NMDA signaling may have more robust long-term effects than a similar adult disruption. Interestingly, we did not find alterations in local oscillatory activity in these regions, suggesting that long-range synchrony may be more sensitive than local synchrony to blockade of NMDAR signaling during adolescence. Given that deficits in long-range coherence are seen in patients with schizophrenia, this manipulation in rodents may prove useful in understanding mechanisms behind this phenomenon. Overall, the experiments presented in this Dissertation provide support for the use of EEG as a cross-species translational tool to study schizophrenia across acute and developmental animal models.