Schizophrenia is a dissociative disorder with both positive and negative symptoms. One negative symptom is a selective spatial memory deficit. We learned about this in our studies of Alzheimer’s disease and found it interesting enough to pursue scientifically. In both disorders, there is hippocampal network dysfunction in the slow gamma range. Go figure! Normally, slow gamma oscillations are strongly associated with accuracy of spatial memory retrieval. In schizophrenia, slow gamma activity is reduced. There is also a reduction in the number of NMDA receptors containing GluN2B subunits at excitatory synapses in the hippocampus. In animal models, when GluN2B expression is experimentally elevated, slow gamma power returns to normal and spatial memory is recovered. Great! But NMDA receptors signal in two different ways, with (ionotropic) or without ion conductance (nonionotropic) into the postsynaptic neurons. So, the slow gamma dysfunction could be due to loss of GluN2B ionotropic or nonionotropic signaling. How do you study that? We approach this with transgenic mice and adenoassociated viral vectors (AAVs) that express chimeric GluN2B subunits to separate the ionotropic and nonionotropic contributions to GluN2B subunit signaling. We have found that increasing the NMDA receptor incorporation of the GluN2B carboxy terminal domain enhances spatial memory relative to wildtype mice (Sanders et al., 2018) and prolongs activity dependent synaptic potentiation (Keith et al., 2024). We are now recording local field potentials from transgenic mice as they perform the Barnes maze (a spatial learning and memory task) to investigate the impacts of chimeric GluN2 subunit expression on hippocampal oscillations associated with spatial memory, including slow gamma. What do you think we will discover?! This project is supported by a generous R21 award from the National Institutes of Health, National Institute of Mental Health (R21 MH135232-01A1).
