Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone.
Frontiers in cellular neuroscience January 1, 2023 Cristina Delgado-Sallent, Thomas Gener, Pau Nebot et al.
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.