NMDA receptor (NMDA-R) hypofunction is a key component of the pathomechanism of cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in human and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast firing interneurons. These neurons are critical for gamma oscillations indicating that pathological changes in gamma synchronization may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. Cortical field potentials were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring antagonists (PEAQX, NVP-AAM077, n=7), NR2B-selective antagonists (ifenprodil, n=6; threoifenprodil, n=4; Ro25-6985, n=8) and a NR2C/D-selective antagonist (PPDA, n=4), along with vehicle and non-selective NMDA-R antagonists (ketamine, n=8, MK801, n=10). I was found that strong aberrant increase in gamma power induced by non-selective NMDA-R antagonists was replicated by blockade of NMDA-Rs containing the NR2A subunit whereas blockade of NR2B, C, or D subunit-containing receptors did not have such effect. The data indicate that major subtype-specific differences in the role of NMDA-Rs on cortical gamma oscillation may have serious implications for the pathomechanism and treatment of cognitive impairment. Specifically, pathologic neuronal synchronization due to NR2A receptor deficiency may contribute to cognitive deficits in schizophrenia.