Dorsal And Ventral Pfc Responses To Working Memory Differ In Schizophrenia

establishing that a modified rodent spatial working memory task, the discrete-trial variable-delay alternation task, had important elements of human working memory paradigms. For example, performance remained submaximal and stable at second-long retention intervals, was dependent on retention interval and proactive inhibition, and on the integrity of the medial prefrontal cortex. Consistent with clinical findings, low dose amphetamine produced a delay-dependent improvement in performance while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted doseand delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR 2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/ kainate antagonist had similar effects as the mGluR2/3 agonist. In contrast, the detrimental effect of NMDA receptor blockade was independent of memory load, with the higher dose resulting in chance-level performance at all retention intervals. These findings suggest the following: (1) activation of NMDA receptors is necessary for the initiation of the mnemonic encoding, (2) during the retention phase, WM is maintained by slow components that include the asynchronous phase of glutamate release resulting in “sustained” (second-long) postsynaptic activation of glutamate receptors, and phasic release of dopamine resulting in activation of D1 receptors.