Blocking NMDA receptors with phencyclidine (PCP) in mice impairs short-term and long-term object recognition memory and disrupts auditory processing, modeling cognitive deficits in schizophrenia. Memory impairments were linked to increased theta oscillations in the medial prefrontal cortex, decreased gamma oscillations and theta-gamma coupling in the dorsal hippocampus, and disrupted communication between the two regions. The atypical antipsychotic risperidone, given daily for two weeks after PCP, rescued memory deficits and partly normalized hippocampal activity but did not fully restore prefrontal cortex or circuit connectivity. Auditory processing deficits were also partially reversed. The findings suggest that NMDA receptor hypofunction disconnects prefrontal-hippocampal circuits, and risperidone may improve cognition by acting on this circuitry.
Psychosis induced by the NMDAR antagonist phencyclidine in mice causes hypersynchronization and disrupted communication between the prefrontal cortex and hippocampus, including increased oscillatory power at delta, high gamma, and high frequencies, aberrant cross-frequency coupling, enhanced cross-regional coupling and phase coherence, and a reversal of the direction of theta-frequency information flow from hippocampus-to-prefrontal-cortex to delta rhythms traveling in the opposite direction. Three antipsychotic drugs—haloperidol, clozapine, and risperidone—rescued most of these changes, suggesting common cellular mechanisms. Selective serotonin receptor agents rescued power, coupling, and phase coherence but not the directionality, indicating additional targets are needed.