DISRUPTED SPATIAL REPRESENTATION RETRIEVAL AND ENCODING IN LARGE NEURONAL POPULATIONS IN HIPPOCAMPAL CA1 UNDER NMDA RECEPTOR BLOCKADE

Hippocampal CA1 networks encode spatial memory through a balance of stability and flexibility that depends critically on NMDA receptor–mediated plasticity. Disruption of this balance is thought to contribute to cognitive disorganization in psychosis. Here, we investigated how a psychosis model induced by systemic NMDA receptor inhibition alters retrieval and encoding of spatial representations using calcium imaging in freely moving GCaMP6f+ mice.
Mice familiarized to linear track were recorded over four days. Each day, they received five familiar track trials and three novel track trials and either i.p. injection of saline or 0.2mg/kg MK-801. Tracking the same CA1 neuronal population across days, we quantified ensemble similarity, firing activity, spatial tuning, and network dynamics.
Under saline, familiar environments showed high congruence across trials. Exposure to novel environments induced quick formation of orthogonalized representations. In contrast, MK-801 suppressed similarity of familiar environment codes to those recorded before and after the injection. Despite this, spatially-modulated firing persisted: place fields remained detectable but were broader and less spatially precise. The novel track representation developed in a less organized way, as the population firing patterns between the three novel track trials correlated less than under saline.
These results show that NMDA inhibition disrupts population code for space without eliminating individual cell spatial coding. It affects the stabilization and contextual specificity of representations, as seen in certain cognitive dysfunctions like psychosis, and demonstrates the efficacy of large population-level calcium imaging for dissecting circuit-level effects of pharmacological perturbations in freely behaving mice models.
Supported by GACR-26-23770S, SVV-263774.