Pierri JN, Chaudry AS, Woo T-U, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry 156: 1709-1719
ABSTRACT 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). "
ABSTRACT: The history of ketamine and phencyclidine from their development as potential clinical anaesthetics, through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The finding of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. This article is protected by copyright. All rights reserved.British Journal of Pharmacology 06/2015; 172(17). DOI:10.1111/bph.13222 · 4.84 Impact Factor
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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). "
ABSTRACT: Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20 years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5′ end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 3.92 Impact Factor
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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 "
ABSTRACT: Schizophrenia is a disease affecting up to 1% of the population. Current therapies are based on the efficacy of chlorpromazine, discovered over 50 years ago. These drugs block dopamine D2-like receptors and are effective at primarily treating positive symptoms in a subset of patients. Unfortunately, current therapies are far from adequate, and novel treatments require a better understanding of disease pathophysiology. Here we review the dopamine, gamma-aminobutyric acid (GABA), and glutamate hypotheses of schizophrenia and describe a pathway whereby a loss of inhibitory signaling in ventral regions of the hippocampus actually drives a dopamine hyperfunction. Moreover, we discuss novel therapeutic approaches aimed at attenuating ventral hippocampal activity in a preclinical model of schizophrenia, namely the MAM GD17 rat. Specifically, pharmacological (allosteric modulators of the α5 GABAA receptor), neurosurgical (deep brain stimulation), and cell-based (GABAergic precursor transplants) therapies are discussed. By better understanding the underlying circuit level dysfunctions in schizophrenia, novel treatments can be advanced that may provide better efficacy and a superior side effect profile to conventional antipsychotic medications.Drug Design, Development and Therapy 07/2014; 8:887-896. DOI:10.2147/DDDT.S42708 · 3.03 Impact Factor