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BackgroundPhencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist impairs cognition remains unknown.MethodsThe effects of PCP were investigated i) on hippocampal CA1 ensemble action potential dischargein vivoin urethane-anesthetized rats and during awake behavior in mice; ii) on synaptic responses inex vivomouse hippocampus slices; iii) in mice on a hippocampus-dependent active place avoidance task that requires cognitive control; and iv) on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects to the effects of inhibitors of protein synthesis, group-1-type metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs.ResultsConsistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity, and impaired active place avoidance, despite learning the task before PCP. Consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression (LTD). Pretreatment with anisomycin or the mGluR1/5-antagonist MPEP, both of which repress translation, prevented the PCP-induced discoordination, and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR-antagonist NVP-AAM077 unbalanced translation that engages the AKT, mTOR and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not.ConclusionsPCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.

Hippocampus is comprised of ∼20% place cells, discharging in cell-specific locations (“place fields”), standardly interpreted as a dedicated neuronal code for space. However, place cell discharge is temporally unreliable across seconds and days, and place fields are multimodal, suggesting an alternative “ensemble cofiring” spatial code with manifold dynamics that does not require reliable spatial tuning. We evaluated these hypotheses using GCaMP6f and miniature microscopes to image mouse CA1 ensemble activity in two environments, across 3 weeks. Both place fields and ensemble coactivity relationships appear to “remap,” being distinct between, and (weakly) similar within environments. Decoding location as well as environment from 1-s ensemble location-specific discharge is effective and improves with experience. Decoding the environment (but not location) from cell-pair coactivity relationships is also effective and improves with experience, even after removing place tuning. Discriminating environments from 1-s ensemble coactivity relies crucially on the cells with the most anti-cofiring cell-pair relationships because ensemble activity is internally-organized on a low-dimensional manifold of non-linear cofiring relationships that intermittently reregisters to environments according to the anti-cofiring subpopulation activity.