Consistent with the PING model, there is ample evidence to suggest that both excitatory glutamatergic and inhibitory GABAergic activity are disturbed in schizophrenia (84, 85). Deficits in excitatory glutamatergic signaling have been identified as a possible core feature behind the pathophysiology of schizophrenia that gave rise to the NMDA receptor hypofunction hypothesis (71). This hypothesis arose from the observation that NMDA receptor antagonists (e.g., ketamine, PCP) can reproduce some of the symptoms of schizophrenia. Subsequent studies have identified widespread dysfunction of NMDA receptors in schizophrenia. Interestingly, given that the GBO is thought to be generated by the activity of inhibitory interneurons, much of the observed dysfunction in NMDA receptors has been specific to inhibitory interneurons themselves. For example, post-mortem analysis of the PFC of schizophrenia patients has shown a 50% reduction in the expression of the NR2A subunit within inhibitory interneurons that express parvalbumin, a calcium binding protein (109). Moreover, chronic NMDA receptor antagonist administration in rodent models reduces the expression of the parvalbumin protein and GAD67 (the primary GABA-synthesizing enzyme glutamic acid decarboxylase) in parvalbumin-positive(+) inhibitory interneurons (110, 111). Acute administration of NMDA receptor antagonists has also been shown to decrease the activity of interneurons with a corresponding increase in the activity of pyramidal cells (70). Thus, NMDA receptor antagonism may reduce the function of inhibitory interneurons which subsequently disinhibits the activity of pyramidal cells. Within the context of schizophrenia, NMDA receptor hypofunction may result in the diminished excitation of inhibitory interneurons within cortical networks.