Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia
Introduction
Dysfunction of inhibitory cortical circuits has emerged as a key substrate for the pathophysiology of cognitive dysfunction in schizophrenia, now recognized as the core clinical feature of the disorder. This perspective has been supported by the multiple reports, from different research groups using complementary methods in separate cohorts of subjects, that schizophrenia is associated with lower tissue levels of the mRNA for the 67 kD isoform of glutamic acid decarboxylase (GAD67; product of the GAD1 gene), the enzyme responsible for most GABA synthesis in the cortex [1]. Consistent with these findings, cortical GAD67 protein levels are also lower in schizophrenia [2, 3]. Together, these data support the hypothesis that the capacity to synthesize cortical GABA is lower in the cerebral cortex of individuals with schizophrenia, and thus that levels of cortical GABA are reduced.
Attempts to test this hypothesis in vivo have included measures of total GABA levels by magnetic resonance spectroscopy. Unfortunately, the results of these studies have been variable, with cortical GABA levels reported to be lower, higher or not different in individuals with schizophrenia relative to comparison subjects [4•]. The apparent inconsistencies in these findings may reflect a number of differences across studies including the cortical region examined, the medication status and age of the subjects, and the specific methods employed [4•]. On the other hand, in vivo electrophysiological measures that index the functional activity of GABA neurons have been more consistent. For example, gamma frequency (30–80 Hz) oscillations require the synchronized inhibition of neighboring populations of pyramidal neurons by the subclass of cortical GABA neurons that express the calcium-binding protein parvalbumin (PV) [5]. In the human prefrontal cortex, gamma oscillations increase in proportion to cognitive task demands, such as working memory load [6], and under such task demands the power of prefrontal gamma band oscillations is reduced in subjects with schizophrenia both in the chronic stage of the illness [7] and in the early stages before the initiation of treatment [8]. Thus, alterations in PV neurons could contribute to gamma oscillation disturbances and cognitive deficits in schizophrenia [9].
Section snippets
Alterations in cortical PV neurons in schizophrenia
Postmortem studies have shown that the number of PV neurons does not differ between subjects with schizophrenia and comparison subjects [10, 11, 12], but these cells do exhibit abnormalities in critical molecular features that are likely to affect their function. For example, in subjects with schizophrenia mRNA levels of GAD67 are markedly lower in a substantial proportion of PV cells [10]. In addition, studies at the tissue, laminar and cellular levels have demonstrated lower levels of PV mRNA
Potential mechanisms for PV cell dysfunction in schizophrenia
A series of recent studies suggest a number of different mechanisms, not mutually exclusive, that could contribute to PV cell alterations in schizophrenia. The lower levels of GAD67 mRNA could reflect disturbances in upstream factors that regulate the GAD1 gene. For example, a variant in the GAD1 gene associated with increased risk for schizophrenia [23] and altered chromatin structures at the GAD1 promoter [24] have been associated with lower levels of GAD67 mRNA in schizophrenia. Recently,
Funding source
Studies by the author cited in this paper were supported by NIH grants MH043784 and MH051234.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
The author appreciates the assistance of Laura English in the preparation of the manuscript.
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