Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone
Delgado-Sallent, Cristina (Institut Hospital del Mar d'Investigacions Mèdiques)
Gener, Thomas (Institut Català de Nanociència i Nanotecnologia)
Nebot, Pau (Institut Hospital del Mar d'Investigacions Mèdiques)
López-Cabezón, Cristina (Universitat Autònoma de Barcelona. Institut de Neurociències)
Puig, Maria Victoria (Institut Català de Nanociència i Nanotecnologia)

Data:	2023
Resum:	N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.
Ajuts:	Agencia Estatal de Investigación PID2019-104683RB-I00
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Atypical antipsychotic drugs ; Auditory evoked potentials ; Hippocampus ; Neural synchrony ; Novel object recognition ; Phencyclidine ; Prefrontal cortex ; Theta and gamma oscillations
Publicat a:	Frontiers in cellular neuroscience, Vol. 17 (march 2023) , ISSN 1662-5102

DOI: 10.3389/fncel.2023.1152248
PMID: 37066076

15 p, 5.4 MB

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