Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation

Area of Science:

• Neuroscience
• Pharmacology
• Cognitive Science

Background:

• Phencyclidine (PCP) is known to induce psychosis and is frequently abused.
• PCP's effects on hippocampal function and cognitive control are well-documented but the underlying mechanisms remain unclear.
• Its role in antipsychotic drug discovery highlights the need to understand its neurobiological impact.

Purpose of the Study:

• To elucidate the mechanisms by which phencyclidine (PCP) impairs cognitive control.
• To investigate PCP's effects on hippocampal ensemble activity, synaptic plasticity, and protein synthesis.
• To determine the role of specific NMDAR subtypes and mGluR1/5 signaling in PCP-induced deficits.

Main Methods:

• In vivo electrophysiology in rats and mice to assess hippocampal CA1 ensemble discharge.
• Ex vivo slice electrophysiology to examine synaptic responses in mouse hippocampus.
• Behavioral testing in mice using an active place avoidance task.
• Analysis of protein synthesis activation and modulation by pharmacological agents.

Main Results:

• PCP caused discoordination of hippocampal ensemble activity, hyperactivity, and impaired performance on a cognitive task.
• PCP exaggerated metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression.
• Inhibition of protein synthesis or mGluR1/5 signaling prevented PCP-induced neural and behavioral impairments.
• PCP's effects were linked to NR2A-containing NMDARs and dysregulated translation machinery (Akt, mTOR, 4EBP1).

Conclusions:

• PCP dysregulates protein synthesis through NR2A-containing NMDARs and mGluR1/5 signaling.
• This dysregulation leads to neural discoordination, which underlies cognitive and sensorimotor impairments.
• Targeting these pathways offers potential therapeutic strategies for PCP-induced effects.