Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation.

Cognitive coordination NR2A Neural discoordination Protein synthesis Translation machinery mGluR1/5

Journal

Biological psychiatry global open science
ISSN: 2667-1743
Titre abrégé: Biol Psychiatry Glob Open Sci
Pays: United States
ID NLM: 9918227369306676

Informations de publication

Date de publication:
Jan 2024
Historique:
received: 09 12 2022
revised: 19 04 2023
accepted: 20 04 2023
medline: 1 2 2024
pubmed: 1 2 2024
entrez: 1 2 2024
Statut: epublish

Résumé

Phencyclidine (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 NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented 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 (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.

Sections du résumé

Background UNASSIGNED
Phencyclidine (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 NMDA receptor (NMDAR) antagonist impairs cognition remains unknown.
Methods UNASSIGNED
The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs.
Results UNASSIGNED
Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented 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 (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not.
Conclusions UNASSIGNED
PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.

Identifiants

DOI: 10.1016/j.bpsgos.2023.04.009 PMID: 38298788 PMC: PMC10829677
pubmed: 38298788
doi: 10.1016/j.bpsgos.2023.04.009
pii: S2667-1743(23)00051-4
pmc: PMC10829677
doi:

Types de publication

Journal Article

Langues

eng

Pagination

252-263

Informations de copyright

© 2023 The Authors.

Auteurs

Eun Hye Park (EH)

Center for Neural Science, New York University, New York, New York.

Hsin-Yi Kao (HY)

Center for Neural Science, New York University, New York, New York.

Hussam Jourdi (H)

Center for Neural Science, New York University, New York, New York.

Milenna T van Dijk (MT)

Center for Neural Science, New York University, New York, New York.
Graduate Program in Neuroscience and Physiology, New York University Langone Medical Center, New York, New York.

Simón Carrillo-Segura (S)

Center for Neural Science, New York University, New York, New York.
Graduate Program in Mechanical and Aerospace Engineering, New York University Tandon School of Engineering, New York, New York.

Kayla W Tunnell (KW)

Center for Neural Science, New York University, New York, New York.

Jeffrey Gutierrez (J)

Center for Neural Science, New York University, New York, New York.

Emma J Wallace (EJ)

Graduate Program in Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.
Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.

Matthew Troy-Regier (M)

Graduate Program in Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.
Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.

Basma Radwan (B)

Graduate Program in Neural Science, Center for Neural Science, New York University, New York, New York.

Edith Lesburguères (E)

Center for Neural Science, New York University, New York, New York.

Juan Marcos Alarcon (JM)

Department of Pathology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.
Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.

André A Fenton (AA)

Center for Neural Science, New York University, New York, New York.
Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.
Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.
Neuroscience Institute, NYU Langone Health, New York, New York.

Classifications MeSH