Normal neurocognitive functioning is contingent upon the integrity of information processing in the cerebral cortex, with specific cortical areas contributing differentially to various aspects of cognition. For instance, the prefrontal cortex (PFC) plays an important role in the temporal organization of behavior, or executive functioning, via working memory [20
]. Working memory is the ability to temporarily maintain “on-line” internal representations of information in the perceptual, cognitive, and emotive domains that are no longer immediately present, for a brief period of up to tens of seconds, in order to guide future behavior [5
]. In other words, the integrity of working memory is critical for the sequential execution of motor or cognitive acts in a goal-directed manner; this capacity forms the basis of a variety of normal daily human activities, such as planning, reasoning, thinking and language. Patients with schizophrenia exhibit impairment in the performance of many of these activities [8
]. In fact, working memory and executive functioning deficits are thought to represent core pathophysiologic or perhaps endophenotypic features of schizophrenia [22
]. Although disturbances of the prefrontal functional architecture have also been implicated in bipolar disorder [53
], working memory, as measured by the delayed response paradigm, seems to be relatively intact in this illness [40
]. Thus, the pathophysiologic nature of neural circuitry disturbances within the PFC may be dissimilar in the two conditions.
Inhibitory interneurons that utilize GABA (γ-aminobutyric acid) as a neurotransmitter play a crucial role in the maintenance of sustained neuronal activation during working memory by dynamically adjusting the conductances of the pyramidal neuronal network. Interestingly, the number of N-methyl-D-aspartate (NMDA) glutamate receptors on GABA neurons appears to be an important determinant of the stability of the network in sustaining working memory [34
]. GABA neurons receive feedback excitatory modulation via local recurrent excitatory projections from the pyramidal neurons they innervate and, at the same time, they are also targets of feedforward excitatory modulation from axonal projections furnished by other pyramidal neurons, located both within the PFC and in other cortical areas [6
]. Furthermore, projections from the thalamus provide additional excitatory drive to GABA cells [63
]. The integrity of working memory and associated functions, such as executive control, depends on the complex interplay of feedback and feedforward mechanisms of modulation of cortical inhibitory activities via activation of glutamate receptors on GABA neurons [11
], which helps to regulate the temporal flow of information between spatially distributed populations of pyramidal neurons in a contextually meaningful manner.
Converging lines of evidence strongly suggest that, in the PFC, functional disturbances of GABA neurons represent a prominent pathophysiologic feature of schizophrenia [1
] and bipolar disorder [24
]. In addition, alterations of glutamatergic modulation of GABA cells could further compromise PFC functions. In fact, in a recent study, we found that in the anterior cingulate cortex the density of GABA cells that expressed the NMDA NR2A subunit was decreased schizophrenia and bipolar disorder [65
]. It is currently unknown whether similar changes also occur in other brain regions, such as the PFC. In this study, we used double in situ hybridization to co-localize the mRNA for the NMDA NR2A subunit and that for the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)67
, in the PFC in a cohort of 60 human subjects (). We found that the pattern of changes in the density of GABA neurons was remarkably similar between schizophrenia and bipolar disorder, but the density of those GABA cells that expressed NR2A was altered in a diagnosis- and laminar-specific manner.
Photomicrograph of a double-labeled neuron with silver grains superimposed onto the digoxigenin reaction product. Scale bar=5 µm.