A New Paradigm for Understanding Gamma-Aminobutyric Acid Cell Pathology in Schizophrenia?

Abstract

p c w t a f r t a r D a T he article by Joshi et al. (1) in this edition of Biological Psychiatry is a provocative study that addresses a long-standing question as to whether gamma-aminobutyric acid (GABA) cell pathology in schizophrenia can be understood within a neurodevelopmental framework. Following initial reports that GABA cells are reduced in number and function in superficial cortical layers in schizophrenics, it was suggested that these changes may be related to disturbed migration during prenatal and early postnatal development (2). Ted Jones and his colleagues provided support for this hypothesis by demonstrating that a reduced density of presumptive interneurons in superficial layers of prefrontal cortex was accompanied by a significant increase in the number of these cells in the subcortical white matter (3). The study by Joshi et al. (1) has taken an important step toward identifying whether a disturbance of cell migration during development may contribute to a redistribution of GABAergic cells in the orbital frontal gyrus (OFG) in schizophrenia. Consistent with the study by Akbarian et al. (3), they report that the numbers of glutamic acid decarboxylase 67 (GAD67) expressing neurons in the superficial portions of the interstitial white matter (IWM) are increased, while those in the superficial layers of the gray matter (GM) in the OFG are decreased in schizophrenia. Joshi et al. (1) also examined the distribution of cells expressing DLX1,2, a developmental marker for the migration of GABA neurons originating in the subventricular zone. These data show that DLX1,2 is not expressed in the superficial IWM but is expressed in gray matter neurons, ones that are localized primarily at the base of the sulci. So, the spatial distribution of GAD67/glutamic acid decarboxylase 65 (GAD65)-expressing cells versus those that express DLX1,2 are fundamentally different in the OFG. Does this difference have some bearing on the potential role of DLX1,2 in the migration of GABA cell precursors into the OFG or perhaps for a broader understanding of GABA dysfunction in the OFG? During the prenatal and early postnatal periods, the number of interneurons increases in an inside-out fashion, with layer III, then layer II, being the last laminae to show a full complement of these cells with a mature pattern of dendritic branching (4). It is generally believed, though, that the evidence is sketchy, that this migration is complete early in life, and that the cells present at this stage will remain in place, unless a pathological process compromises the integrity of the tissue. Decreased numbers of GABA neurons in the superficial layers may be related to a loss of these cells, while the concomitant occurrence of increased numbers in the IWM may suggest that a disturbance in their migration to the GM may have occurred. If this interpretation were correct, it would still be unclear as to whether it represents a disturbance of normal ontogenesis early in life or whether perhaps there may have been a failure of migration during adulthood. If the latter were the case, it would have to be assumed that GABA cells in the superficial layers of the GM are being lost during the adult period. This could occur whether