Trends in Neurosciences
ReviewSpecial Issue: Neuropsychiatric DisordersCortical parvalbumin interneurons and cognitive dysfunction in schizophrenia
Introduction
Psychosis (e.g. hallucinations, delusions and disorganized behavior) is the most striking clinical feature of schizophrenia, but impairments in cognition are now recognized as the core domain of dysfunction in the illness [1]. Cognitive deficits are present and progressive years before the onset of psychosis [2] and the degree of cognitive impairment is the best predictor of long-term functional outcome [3]. The range of cognitive deficits in schizophrenia suggests an overarching alteration in cognitive control; that is, the ability to adjust thoughts or behaviors to achieve goals [4]. Cognitive control depends on the coordinated activity of several brain regions, including the dorsolateral prefrontal cortex (DLPFC) [5], and gamma frequency (30–80 Hz) oscillations in DLPFC neural networks are thought to be a key neural substrate for cognition [6]. Consistent with these observations, when performing tasks that require cognitive control, individuals with schizophrenia exhibit altered activation of the DLPFC [7] and lower power of frontal lobe gamma oscillations 8, 9.
Because cortical gamma oscillations require the strong and synchronous inhibition of networks of pyramidal neurons (reviewed in [10]), deficient GABA neurotransmission in the DLPFC has been hypothesized to contribute to altered gamma oscillations and impaired cognition in schizophrenia [11]. Consistent with this interpretation, manipulations in animal models that reduce GABA-mediated inhibition diminished gamma oscillations [12] and impaired cognitive function 13, 14, 15, 16. In addition, in individuals with schizophrenia, negative modulation of GABAergic neurotransmission exacerbated symptoms [17], whereas positive modulation was associated with increased frontal lobe gamma oscillations during a cognitive control task [18].
However, surprising recent findings regarding the functional properties of certain subtypes of cortical interneurons and new observations regarding cell type-specific alterations in markers of GABAergic neurotransmission in schizophrenia require a new conceptualization of the role of altered cortical GABAergic signaling in the cognitive deficits of schizophrenia. Consequently, here we (i) review recent findings both from cellular physiology experiments and postmortem studies of schizophrenia that demonstrate the limitations of existing circuitry models of cognitive dysfunction in schizophrenia based on earlier data; (ii) propose a new pathophysiological model of the role of altered GABA neurotransmission in cortical circuitry dysfunction in schizophrenia; and (iii) discuss the key research questions raised by the new data and model.
Section snippets
Deficient cortical GABA synthesis is a conserved feature of schizophrenia
GABAergic signaling is regulated, in part, by the enzymatic activity of two isoforms of glutamic acid decarboxylase (GAD), which differentially contribute to GABA synthesis. In mice, deletion of the gene encoding the 67-kDa isoform of GAD (GAD67) results in a 90% reduction in brain GABA levels and is embryonically lethal [19], whereas deletion of the GAD65 gene is associated with only a 20% reduction in total brain GABA [20] and normal survival. In multiple studies using a variety of
GAD67 deficit is prominent in parvalbumin-positive interneurons
Understanding the functional significance of lower cortical GAD67 levels requires knowledge of the affected class of interneurons. In schizophrenia, GAD67 mRNA levels are markedly lower only in 25–35% of DLPFC interneurons 37, 38, and GAD67 mRNA is not detectable in approximately 50% of the subset of interneurons that express the calcium-binding protein parvalbumin (PV) [39]. Levels of PV mRNA are also lower in schizophrenia 24, 40, 41, but the densities of neurons labeled for either PV mRNA
Alterations in PVChCs in schizophrenia: increasing pyramidal cell excitation?
In schizophrenia, the density of PVChC axon cartridges that are immunoreactive for the GABA membrane transporter 1 (GAT1) is reduced in DLPFC layers 2–4 47, 48 (Figure 1). In layers 2 and superficial 3 of subjects with schizophrenia, the lower density of GAT1-labeled cartridges is inversely correlated with an increase in the density of AISs that are immunoreactive for the α2 subunit of the GABAA receptor [49] (Table 1). Consistent with these findings, GABAA α2 subunit mRNA levels are elevated
Alterations in PVBCs in schizophrenia: decreasing pyramidal cell inhibition?
The PV neurons with reduced GAD67 mRNA expression in schizophrenia do include PVBCs, as lower GAD67 protein levels have been found in PVBC axon terminals (identified by excluding PVChC axon cartridges) in DLPFC layers 3–4 in subjects with schizophrenia [23] (Figure 2). The cell-type specificity of this finding was supported by the observation that the GAD67 protein deficit in these terminals was approximately ten times greater than in the total DLPFC gray matter from the same subjects [23].
Role of PVBCs in lower DLPFC gamma oscillation power in schizophrenia
The findings summarized above suggest that several molecular alterations in different cell types converge to weaken PVBC inputs to pyramidal neurons in DLPFC layer 3 in schizophrenia. Interestingly, PVBCs play a critical role in the generation of cortical gamma band oscillations 10, 45, 46. For example, the α1-containing GABAA receptors that are postsynaptic to PVBC inputs in hippocampal pyramidal cells produce currents with a decay period appropriate for gamma oscillations [10]. In addition,
PV interneurons and cortical excitatory-inhibitory balance in schizophrenia
One possible upstream factor might be the dendritic spine deficit on layer 3 pyramidal neurons [85], which could lead to a net reduction in local DLPFC excitatory activity and impaired gamma oscillations. According to the pyramidal-interneuron network gamma (PING) model of gamma oscillations, PVBCs are recruited by phasic, glutamatergic inputs from pyramidal neurons, and PVBCs provide strong and fast (i.e. GABAA α1-receptor-mediated) feedback inhibition to pyramidal neurons [86]. The divergent
Disclosure statement
D.A.L. currently receives investigator-initiated research support from Bristol-Myers Squibb (BMS), Curridium and Pfizer and, in 2009–2011, served as a consultant in the areas of target identification and validation and new compound development to BioLine RX, BMS, Merck and SK Life Science.
Acknowledgments
The authors thank Mary Brady for technical assistance. The work conducted by the authors and cited in this review was supported by National Institutes of Health (NIH) grants MH084053 and MH043784. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the National Institute of Mental Health.
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