N-methyl-D-aspartate receptor expression in parvalbumin-containing inhibitory neurons in the prefrontal cortex in bipolar disorder.

Inhibitory neural circuits in the cerebral cortex have been established as functionally disturbed in schizophrenia, but recent studies suggest that disturbances of inhibitory neurons may also contribute to the pathophysiology of bipolar disorder (1-5). Because inhibitory neurons are functionally and connectionally diverse, with different subsets of these neurons regulating distinct aspects of information flow in the cortex (6), it is imperative to determine the specific subsets of these neurons that are affected in order to be able to truly appreciate the pathophysiologic consequences of the functional disturbances of these neurons. Toward this end, findings of postmortem studies in the past few years have led to the general agreement that inhibitory neurons that contain the calcium buffering protein parvalbumin (PV), which exhibit fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons (7, 8), are functionally compromised in schizophrenia (5). For example, in the prefrontal cortex (PFC), the expression of the messenger RNA (mRNA) for PV and the γ-aminobutyric acid (GABA) synthesizing enzyme glutamatic acid decarboxylase (GAD)67 in the PV-containing neurons appears to be significantly decreased in subjects with schizophrenia (9). Furthermore, we have recently found that, in schizophrenia, the expression of the mRNA for the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor in these neurons also appears to be decreased (10). This latter finding supports the notion that reduced glutamatergic inputs to PV neurons via the NMDA receptor contributes to the downregulation of PV and GAD67 transcripts (11, 12) and hence plays a central role in the functional disturbances of PV neurons in schizophrenia (13, 14). Recently, we found that, in bipolar disorder, the expression of the mRNA for the GluR5 subunit of the kainate class of glutamate receptor in GABA neurons was decreased in the anterior cingulate cortex (15), whereas the expression of NR2A mRNA in GABA neurons in the PFC was undisturbed (1). Therefore, it may be that, in bipolar disorder, glutamatergic regulation of GABA neurons is disturbed only in the anterior cingulate cortex, but not in the PFC. However, if NR2A expression is altered in only a subset of GABA neurons in the PFC, depending upon the magnitude of change in transcript expression and the percentage of the subset of neurons that is affected, it may not be detectable when the entire population of GABA neurons is examined. In this study, we investigated whether NR2A expression might be altered in the subset of GABA neurons that express PV, which constitute roughly 20-50 % of all GABA neurons in the primate PFC (16). Using double in situ hybridization to colocalize the mRNA for PV and NR2A in a cohort of subjects with bipolar disorder and demographically matched normal control subjects, we found that the expression of NR2A mRNA in PV neurons in the PFC was unchanged in bipolar disorder. Thus, although inhibitory neural transmission in the cerebral cortex is disturbed in both bipolar disorder and schizophrenia (1-5), the manner in which glutamatergic regulation of inhibitory neural circuits is impaired appears to be disease- and region-specific.