Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects.
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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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 his-tone 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 kilo-bases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including devel-opmentally 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. © 2014 Elsevier B.V. All rights reserved. 1. GABAergic dysfunction in schizophrenia — a brief chronology Schizophrenia (SCZ) — a major psychiatric disorder with symptoms of delusions, hallucinations disorganized thought and affect, social with-drawal and apathy — lacks unifying neuropathology (Dorph-Petersen and Lewis, 2011; Catts et al., 2013), or narrowly defined genetic risk architectures and disease etiologies (Rodriguez-Murillo et al., 2012; Andreassen et al., 2014). Yet, clinical and translational research con-ducted over the last 40 years is beginning to identify major building blocks within the complex pathophysiology of SCZ. As highlighted in the various articles in this Special Issue of Schizophrenia Research, one such building block is the inhibitory GABAergic circuitry in the cerebral cortex. While the primary focus of our review will be on the transcrip-tional dysregulation of the glutamic acid decarboxylase 1 (GAD1) gene, encoding the 67 KDa GABA synthesis enzyme, we will begin with a brief synopsis of past studies in pursuit of the 'GABAergic hypothesis of SCZ', which proposes that GABAergic systems could play a key role in the pathophysiology of SCZ. This idea is not new. Thus, 25 years after the first reports described the relatively large amounts of GABA and high levels of glutamic acid decarboxylase (GAD) in the brain (Roberts and Frankel, 1950, 1951), the role of inhibitory inputs to midbrain dopaminergic neurons was hypothesized to be the key mechanism responsible for excessive and dysregulated dopaminergic activity in psychosis (Stevens et al., 1974; Smythies et al., 1975). While it was quickly recognized that a generalized deficit in GABA sig-naling is not a characteristic of SCZ — as the symptoms of psychosis remained unresponsive to GABA agonists in early clinical trials (Tamminga et al., 1978) — the idea of region-specific dysfunctions of GABA systems nonetheless continued, up to the present day, to main-tain significant traction and in fact, emerged as one of the most popular hypotheses in SCZ research. For example, several studies reported a decrease in GABA levels and GAD activity in the medial temporal lobe, thalamus and ventral striatum of the SCZ postmortem brain (Bird et al., 1977; Perry et al., 1979; Spokes et al., 1980) albeit other investiga-tors reported negative findings (Cross et al., 1979). There were also re-ports on low GABA levels in the cerebrospinal fluid in at least a subset of patients diagnosed with SCZ (Lichtshtein et al., 1978; van Kammen et al., 1982). Following these early studies on GABA and GAD quantifica-tions in the schizophrenic brain, several papers explored alterations in the inhibitory system in the context of abnormal circuitry. This type of work was mainly focused on the cerebral cortex and hippocampus, starting with Benes' model proposing excessive excitatory and insuffi-cient inhibitory signaling in the upper layers of the cerebral cortex due to a possible loss of GABAergic neurons and/or supranormal numbers or densities of glutamatergic afferent input into the same cortical layers (Benes et al., 1992a,b). There is also an ongoing discussion if and how decreased expression of GABAergic marker genes in the cerebral cortex Schizophrenia Research xxx (2014) xxx–xxx ⁎ Corresponding author.Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 4.43 Impact Factor
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ABSTRACT: A variety of anatomical and physiological evidence suggests that the brain performs computations using motifs that are repeated across species, brain areas, and modalities. The computational architecture of cortex, for example, is very similar from one area to another and the types, arrangements, and connections of cortical neurons are highly stereotyped. This supports the idea that each cortical area conducts calculations using similarly structured neuronal modules: what we term canonical computational motifs. In addition, the remarkable self-similarity of the brain observables at the micro-, meso- and macro-scale further suggests that these motifs are repeated at increasing spatial and temporal scales supporting brain activity from primary motor and sensory processing to higher-level behaviour and cognition. Here, we briefly review the biological bases of canonical brain circuits and the role of inhibitory interneurons in these computational elements. We then elucidate how canonical computational motifs can be repeated across spatial and temporal scales to build a multiplexing information system able to encode and transmit information of increasing complexity. We point to the similarities between the patterns of activation observed in primary sensory cortices by use of electrophysiology and those observed in large scale networks measured with fMRI. We then employ the canonical model of brain function to unify seemingly disparate evidence on the pathophysiology of schizophrenia in a single explanatory framework. We hypothesise that such a framework may also be extended to cover multiple brain disorders which are grounded in dysfunction of GABA interneurons and/or these computational motifs. Copyright © 2015. Published by Elsevier Ltd.Neuroscience & Biobehavioral Reviews 05/2015; DOI:10.1016/j.neubiorev.2015.04.014 · 10.28 Impact Factor
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ABSTRACT: Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients – a critical goal in order to evaluate interventions that would target GABAergic deficits – presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia.Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.011 · 4.43 Impact Factor