In the prefrontal cortex, NMDA receptors are important for normal prefrontal functions such as working memory, and their dysfunction plays a key role in the pathological processes of psychiatric disorders such as schizophrenia. Little is known, however, about the synaptic properties of NMDA receptors in the local circuits of recurrent excitation, a leading candidate mechanism underlying working memory. We investigated the NMDA receptor-mediated currents at monosynaptic connections between pairs of layer 5 pyramidal neurons. We found that NMDA receptor-mediated currents at prefrontal synapses in the adult, but not young, rats exhibit a twofold longer decay time-constant and temporally summate a train of stimuli more effectively, compared to those in the primary visual cortex. Experiments with pharmacological, immunocytochemical, and biochemical approaches further suggest that, in the adult animals, neurons express significantly more NR2B subunits in the prefrontal cortex than the visual cortex. The NR2B-rich synapses in the prefrontal circuitry may be critically implicated in online cognitive computations and plasticity in learning, as well as psychiatric disorders.cortical development ͉ persistent activity ͉ working memory ͉ recurrent excitation W hat are the microcircuit properties that enable the prefrontal cortex (PFC) to subserve cognitive functions such as working memory and decision making in contrast to early sensory coding and processing in primary sensory areas? To address this central question, physiologists have focused on a salient feature of PFC, namely self-sustained persistent activity, as a candidate neural mechanism for short-term working memory in primates (1-3) and rodents (4). It has been hypothesized that persistent activity is generated by sufficiently strong recurrent excitation among prefrontal neurons (5). The N-methyl-Daspartate receptors (NMDARs) may be critically involved in persistent activity, as indicated by the findings that NMDAR antagonists impaired performance on delayed response tasks in rat PFC (6, 7). Recently, computational models confirmed that only the slow kinetics of NMDARs could stabilize the active maintenance of memory trace (8-10), and their voltage dependences could enhance the stimulus selectivity of persistent activity (11). Therefore, modeling work suggests that a distinctive feature of PFC is its slow reverberating neural dynamics that depend on the NMDARs in the local recurrent circuits.This raises the question of whether PFC neurons are endowed with a substantially higher number of NMDARs, or with NMDARs that express distinct biophysical properties, compared with those in a sensory area such as the primary visual cortex V1 (10). One anatomical study has reported a higher level of mRNA for NMDARs in PFC than in other cortices in human postmortem brain tissues (12). Physiologically, little is known about the functional properties of NMDARs in the prefrontal local recurrent circuits. Because prefrontal functions mature more slowly than the visual cortex, and thi...

N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on γ-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to 2D, exhibited inverted-∪ dose-dependent changes in response to MK-801 treatment in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.