Pierri JN, Chaudry AS, Woo T-UW, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry 156: 1709-1719

Department of Psychiatry, University of Pittsburgh, PA 15213, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 12/1999; 156(11):1709-19.
Source: PubMed


Abnormalities in prefrontal cortical gamma-aminobutyric acid (GABA) neurotransmission may contribute to cognitive dysfunction in schizophrenia. The density of chandelier neuron axon terminals (cartridges) immunoreactive for the GABA membrane transporter (GAT-1) has been reported to be reduced in the dorsolateral prefrontal cortex of schizophrenic subjects. Because cartridges regulate the output of pyramidal cells, this study analyzed the laminar distribution of GAT-1-immunoreactive cartridges to determine whether certain subpopulations of pyramidal cells are preferentially affected.
Measurements were made of the density of GAT-1 -immunoreactive cartridges in layers 2-3a, 3b-4, and 6 of dorsolateral prefrontal cortex area 46 in 30 subjects with schizophrenia, each of whom was matched to one normal and one psychiatric comparison subject. GAT-1-immunoreactive cartridge density was also examined in monkeys chronically treated with haloperidol.
Relative to both comparison groups, the schizophrenic subjects had significantly lower GAT-1-immunoreactive cartridge density in layers 2-3a and 3b-4. The decrease was most common and most marked in layers 3b-4, where 80% of the schizophrenic subjects exhibited an average 50.1% decrease in cartridge density in comparison with the matched normal subjects. In contrast, GAT-1-immunoreactive cartridge density was unchanged in the haloperidol-treated monkeys.
These findings demonstrate that the density of GAT-1-immunoreactive cartridges is reduced in the majority of schizophrenic subjects and that this alteration may most prominently affect the function of pyramidal cells located in the middle cortical layers. This abnormality may reflect a number of underlying deficits, including a primary defect in dorsolateral prefrontal cortex circuitry or a secondary response to altered thalamic input to this region.

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    • "Decreased chandelier synapses and up-regulation of GABA receptors Woo et al., 1998; Volk et al., 2002 Pierri et al., 1999; Abe et al., 2000; Wang et al., 2008; du Bois et al., 2009; Beninger et al., 2010 Disinhibition increasing glutamate release with risk of excitotoxicity via AMPA receptors Harrison and Weinberger, 2005; Coyle, 2012; Kraguljac et al., 2013; Poels et al., 2014 Secondly, drug discrimination tests for phencyclidine showed that other arylcyclohexylamines, and many of the above benzomorphans, generalized to the subjective phencyclidine cue (Holtzman, 1980). In the following few years, cross generalization within the arylcyclohexylamines, sigma opiates, dioxolanes and morphinans in rats, pigeons and monkeys was well documented (Holtzman, 1980; 1982; Brady and Balster, 1981; Herling et al., 1981; Shannon, 1981; 1982a,b; 1983; Brady et al., 1982a,b; White and Holtzman, 1982). "
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    • "At the core of this model is a deficit in perisomatic inhibition of cortical pyramidal neurons that involves their axon initiating segments (AISs) as a key control point for the output of cortical information processing (Lewis et al., 2005). The AIS is innervated by a specialized subtype of GABAergic interneuron, the chandelier cell, which is thought to be one of the interneuron types that are dysfunctional in the SCZ cerebral cortex as evidenced by molecular alterations both on the pre-and postsynaptic site of the AIS (Woo et al., 1998; Pierri et al., 1999; Volk et al., 2002). Importantly, these postmortem studies, together with related work in preclinical model systems, paved the way for clinical trials and novel treatment approaches aimed at alleviating GABAergic deficits at the AIS and other key nodes of the cortical inhibitory system (Lewis et al., 2008; Geffen et al., 2012; Radhu et al., 2012; Stan and Lewis, 2012; Lett et al., 2014; Rowland et al., 2013; Rudolph and Mohler, 2014). "
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    • "The cortex and hippocampus both contain interneurons that differentially express calcium binding proteins (PV, calretinin, calbindin) and neuropeptides (somatostatin, neuropeptide Y) with distinct cell types playing a vital role in inhibitory control over pyramidal cell activity in both regions.71,76–78 This is important, as it appears that the GABAergic dysfunction in schizophrenia is restricted to subpopulations of interneurons; ie, those containing PV or somatostatin.78–80 PV containing interneurons are fast firing, perisomatic targeting, and are thus situated to regulate pyramidal cell firing.71,75,81 "
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