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Cereb Cortex. 2015 May;25(5):1348-61. doi: 10.1093/cercor/bht329. Epub 2013 Dec 4.

Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801.

Author information

1
INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Paris Descartes (Paris 5), Paris, France.
2
INSERM UMRS 952, Paris, France CNRS UMR 7224, Paris, France Université Pierre et Marie Curie (UPMC) (Paris 6), Paris, France.
3
Department of Experimental Neurophysiology, Ruhr University, Bochum, Germany and.
4
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.

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.

KEYWORDS:

MK-801; NMDA receptor hypofunction; long-term potentiation; prefrontal cortex; schizophrenia

PMID:
24304584
DOI:
10.1093/cercor/bht329
[Indexed for MEDLINE]

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