title: Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801.
abstract: Noncompetitive N-methyl-d-aspartate receptor antagonists such as phencyclidine and MK-801 are known to impair cognitive function in rodents and humans, and serve as a useful tool to study the cellular basis for pathogenesis of schizophrenia cognitive symptoms. In the present study, we tested in rats the effect of MK-801 on ventral hippocampus (HPC)-medial prefrontal cortex (mPFC) synaptic transmission and the performance in 2 cognitive tasks. We found that single injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC-mPFC response, which shares the common expression mechanisms with long-term potentiation (LTP). But unlike LTP, its induction required no enhanced or synchronized synaptic inputs, suggesting aberrant characteristics. In parallel, rats injected with MK-801 showed impairments of mPFC-dependent cognitive flexibility and HPC-mPFC pathway-dependent spatial working memory. The effects of MK-801 on HPC-mPFC responses and spatial working memory decayed in parallel within 24 h. Moreover, the therapeutically important subtype 2/3 metabotropic glutamate receptor agonist LY379268, which blocked MK-801-induced potentiation, ameliorated the MK-801-induced impairment of spatial working memory. Our results show a novel form of use-independent long-lasting potentiation in HPC-mPFC pathway induced by MK-801, which is associated with impairment of HPC-mPFC projection-dependent cognitive function.
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Paris Descartes (Paris 5), Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Blot
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kimura
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Experimental Neurophysiology, Ruhr University, Bochum, Germany and.
authors.forename: Anne
authors.initials: A
authors.lastname: Kemp
authors.affiliation: Department of Experimental Neurophysiology, Ruhr University, Bochum, Germany and.
authors.forename: Denise
authors.initials: D
authors.lastname: Manahan-Vaughan
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France Department of Psychiatry, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Giros
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tzavara
authors.affiliation: INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France.
authors.forename: Satoru
authors.initials: S
authors.lastname: Otani
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D065852:Spatial Memory / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D016291:Dizocilpine Maleate
keywords: MK-801; NMDA receptor hypofunction; long-term potentiation; prefrontal cortex; schizophrenia