38We used the psychotomimetic phencyclidine (PCP) to investigate the relationships between 39 cognitive behavior, coordinated neural network function and information processing within the 40 hippocampus place cell system. We report in rats that PCP (5mg/kg i.p.) impairs a well-learned 41 hippocampus-dependent place avoidance behavior in rats that requires cognitive control, even 42 when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium 43 gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive 44 impairment caused by systemic PCP administration. PCP discoordinates theta-modulated 45 medium and slow gamma oscillations in CA1 local field potentials (LFP) such that medium 46 gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell 47 firing fields are preserved under PCP but the drug discoordinates the sub-second temporal 48 organization of discharge amongst place cells. This discoordination causes place cell ensemble 49 representations of a familiar space to cease resembling pre-PCP representations, despite 50 preserved place fields. These findings point to the cognitive impairments caused by PCP arising 51 from neural discoordination. PCP disrupts the timing of discharge with respect to the sub-second 52 timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from 53 local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as 54 the root of PCP-induced cognitive impairment. 55 56 Kao et al 4 SIGNIFICANCE STATEMENT 57 58Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma 59 oscillations in the local field potential, and the discharge of a subset of pyramidal neurons called 60 "place cells" is spatially organized such that discharge is restricted to locations called a cell's 61 "place field." Because this temporal coordination and spatial discharge organization is thought to 62 represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt 63 cognitive behavior and assess the importance of neural coordination and place fields for spatial 64 cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal 65 discharge, without disrupting firing fields. These findings dissociate place fields from spatial 66 cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial 67 cognition. 69 70 Place cells are hippocampus principal cells that discharge in 'place fields' that map discharge to 71 locations, making place cell studies de facto investigations of what information the hippocampus 72 represents and how that information is represented (Friston

Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery, but how this uncompetitive NMDA-receptor antagonist impairs cognition remains unknown. Using rats and mice, we report that, consistent with ionotropic actions, PCP discoordinated hippocampus CA1 action potential discharge and impaired a well-learned hippocampus-dependent active place avoidance that requires cognitive control. However, consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR-LTD. Pretreatment with anisomycin or the group I mGluR antagonist MPEP, both of which repress translation, prevented the discoordination and PCP-induced cognitive and sensorimotor impairments. Both PCP and the NR2A-containing NMDA-receptor 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. We conclude that PCP dysregulates translation acting through NR2A receptor subtypes recruiting group 1 mGluR signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.