Phencyclidine disrupts neural coordination and cognitive control by dysregulating translation

Abstract

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.