Modulation of Hippocampus–Prefrontal Cortex Synaptic Transmission and Disruption of Executive Cognitive Functions by MK-801

-aspartate receptor antagonists such asphencyclidine and MK-801 are known to impair cognitive function inrodents and humans, and serve as a useful tool to study the cellularbasis for pathogenesis of schizophrenia cognitive symptoms. In thepresent study, we tested in rats the effect of MK-801 on ventral hip-pocampus (HPC)–medial prefrontal cortex (mPFC) synaptic trans-mission and the performance in 2 cognitive tasks. We found thatsingle injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC–mPFC response, which shares thecommon expression mechanisms with long-term potentiation (LTP).ButunlikeLTP,itsinduction requiredno enhancedorsynchronizedsy-naptic inputs, suggesting aberrant characteristics. In parallel, ratsinjected with MK-801 showed impairments of mPFC-dependent cog-nitive flexibility and HPC–mPFC pathway-dependent spatial workingmemory. The effects of MK-801 on HPC–mPFC responses and spatialworking memory decayed in parallel within 24 h. Moreover, thetherapeutically important subtype 2/3 metabotropic glutamate recep-tor agonist LY379268, which blocked MK-801-induced potentiation,ameliorated the MK-801-induced impairment of spatial workingmemory. 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: long-term potentiation, MK-801, NMDAreceptor hypofunction,prefrontal cortex, schizophreniaIntroductionCognitive symptoms of schizophrenia, labeled often as impair-ment of executive function (Elvevag and Goldberg 2000), arelargely resistant to the treatment with known antipsychotics.Establishing effective treatment methods for the cognitivesymptoms is thus keenly awaited. For this purpose, under-standing the cellular and molecular bases of the symptomswould be critical.Glutamatergic dysfunction exists in many psychiatric dis-orders such as frontotemporal degeneration and Alzheimer’sdisease (Hu et al. 2012; Seltman and Matthews 2012), whereabnormal glutamatergic neurotransmission may underlie thedisease onset. Regarding schizophrenia pathogenesis, a focusalso can be made on the “glutamatergic hypothesis,” whichderived from the well-known observation that noncompetitiveN-methyl-