In mice with NMDAR hypofunction induced by subchronic phencyclidine (PCP), memory and auditory perception impairments are linked to disrupted connectivity between the medial prefrontal cortex and the dorsal hippocampus. Short-term memory relies on high gamma connectivity from the prefrontal cortex to the hippocampus, while long-term memory retrieval depends on theta connectivity from the hippocampus to the prefrontal cortex. Subchronic PCP impairs both short-term and long-term memory, increases prefrontal activity, decreases hippocampal activity, and disrupts this connectivity. Two weeks of daily risperidone rescues memory deficits, attenuates hippocampal desynchronization, and also ameliorates auditory perception impairments and their neural correlates.
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.