Abstract
Schizophrenia is a brain disorder associated with cognitive deficits that severely affect the patients' capacity for daily functioning. Whereas our understanding of its pathophysiology is limited, postmortem studies suggest that schizophrenia is associated with deficits of GABA-mediated synaptic transmission. A major role of GABA-mediated transmission may be producing synchronized network oscillations which are currently hypothesized to be essential for normal cognitive function. Therefore, cognitive deficits in schizophrenia may result from a GABA synapse dysfunction that disturbs neural synchrony. Here, we highlight recent studies further suggesting alterations of GABA transmission and network oscillations in schizophrenia. We also review current models for the mechanisms of GABA-mediated synchronization of neural activity, focusing on parvalbumin-positive GABA neurons, which are altered in schizophrenia and whose function has been strongly linked to the production of neural synchrony. Alterations of GABA signaling that impair gamma oscillations and, as a result, cognitive function suggest paths for novel therapeutic interventions.
Highlights
Schizophrenia is a severe brain disorder that afflicts 0.5– 1% of the world’s population and that is typically first diagnosed in late adolescence or early adulthood
The findings reviewed here suggest that alterations of GABA transmission produce cognitive deficits in schizophrenia by altering the circuit mechanisms of gamma oscillations
The proposal that GABA alterations are linked to altered gamma oscillations and cognition is supported, at least in part, by animal model studies showing that producing a functional loss of GABA-mediated inhibition diminishes gamma oscillations [246] and impairs cognitive function [247, 248]
Summary
Schizophrenia is a severe brain disorder that afflicts 0.5– 1% of the world’s population and that is typically first diagnosed in late adolescence or early adulthood. The multicenter, NIMH-funded Clinical Antipsychotic Trials in Intervention Effectiveness project recently found that newer atypical antipsychotics are not significantly more effective for treating psychosis than older typical antipsychotic medications and showed little benefit for improving cognitive symptoms [2, 3] These findings highlight the need to develop novel therapeutic interventions for schizophrenia [4, 5]. This paper reviews recent evidence further indicating that in subjects with schizophrenia cognitive dysfunction is associated with alterations of oscillations in the gamma frequency band (30–80 Hz), which are normally induced during tasks that engage cognition [10] It reviews the cellular and molecular machinery involved in GABA-mediated synaptic transmission and the mechanisms by which GABA-mediated inhibition may synchronize neural activity in cortical circuits, focusing on the role of parvalbumin- (PV-) positive GABA neurons, whose function has been increasingly linked to the production of synchronized gamma oscillations. Alterations of GABA signaling that impair gamma oscillations and cognitive function in schizophrenia suggest potential paths for therapeutic interventions
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