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Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia.

ABSTRACT: The axons of chandelier cells (ChCs) target the axon initial segment of pyramidal neurons, forming an array of boutons termed a cartridge. In schizophrenia, the density of cartridges detectable by gamma-aminobutyric acid (GABA) membrane transporter 1 immunoreactivity is lower, whereas the density of axon initial segments detectable by immunoreactivity for the ?2 subunit of the GABAA receptor is higher in layers 2/superficial 3 of the prefrontal cortex. These findings were interpreted as compensatory responses to lower GABA levels in ChCs. However, we recently found that in schizophrenia, ChC cartridge boutons contain normal levels of the 67 kDa isoform of glutamic acid decarboxylase (GAD67) protein, the enzyme responsible for GABA synthesis in these boutons. To understand these findings we quantified the densities of ChC cartridges immunoreactive for vesicular GABA transporter (vGAT+), which is present in all cartridge boutons, and the subset of cartridges that contain calbindin (CB+).Prefrontal cortex tissue sections from 20 matched pairs of schizophrenia and unaffected comparison subjects were immunolabeled for vGAT, GAD67, and CB.The mean density of vGAT+/CB+ cartridges was 2.7-fold higher, exclusively in layer 2 of schizophrenia subjects, whereas the density of vGAT+/CB- cartridges did not differ between subject groups. Neither vGAT, CB, or GAD67 protein levels per ChC bouton nor the number of boutons per cartridge differed between subject groups.Our findings of a greater density of CB+ ChC cartridges in prefrontal cortex layer 2 from schizophrenia subjects suggests that the normal developmental pruning of these cartridges is blunted in the illness.

SUBMITTER: Rocco BR

PROVIDER: S-EPMC5374057 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia.

Rocco Brad R BR DeDionisio Adam M AM Lewis David A DA Fish Kenneth N KN

Biological psychiatry 20160929 1

<h4>Background</h4>The axons of chandelier cells (ChCs) target the axon initial segment of pyramidal neurons, forming an array of boutons termed a cartridge. In schizophrenia, the density of cartridges detectable by gamma-aminobutyric acid (GABA) membrane transporter 1 immunoreactivity is lower, whereas the density of axon initial segments detectable by immunoreactivity for the α2 subunit of the GABA<sub>A</sub> receptor is higher in layers 2/superficial 3 of the prefrontal cortex. These finding ...[more]

PMID: 27884423

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Project description:Disturbed cortical ?-aminobutyric acid (GABA) neurotransmission in schizophrenia is evident from lamina- and cell type- specific alterations in presynaptic markers. In the dorsolateral prefrontal cortex (DLPFC), these alterations include lower transcript expression of glutamic acid decarboxylase (GAD67) and somatostatin (SST), a neuropeptide expressed in the Martinotti subpopulation of GABA neurons whose axons innervate the distal apical dendrites of pyramidal neurons. However, whether the alterations in SST-containing interneurons are associated with changes in post-synaptic receptors for SST has not been examined. Thus, we used in situ hybridization to quantify the mRNA expression levels of SST receptors subtype 1 (SSTR1) and subtype 2 (SSTR2) in DLPFC area 9 from 23 matched pairs of subjects with schizophrenia and normal comparison subjects. We also assessed the effects of potential confounding variables within the human subjects and in brain specimens from macaque monkeys with long term exposure to antipsychotic drugs. SSTR1 mRNA levels did not differ between subject groups. In contrast, mean cortical SSTR2 mRNA levels were significantly 19% lower in the subjects with schizophrenia. Laminar and cellular level analyses revealed that lower SSTR2 mRNA levels were localized to pyramidal cells in cortical layers 5-6. Expression of SSTR2 mRNA did not differ between monkeys exposed chronically to high doses of haloperidol or olanzapine and control animals, or between subjects with schizophrenia on or off antipsychotic medications at the time of death. However, levels of SSTR2 mRNA were significantly 37.6% lower in monkeys exposed chronically to low dose haloperidol, suggesting that the lower levels of SSTR2 mRNA selectively in pyramidal neurons in DLPFC layers 5-6 in schizophrenia should be interpreted with caution. In concert with prior findings of lower SST mRNA expression in the same subjects, the results of this study suggest the convergence of pre- and post-synaptic mechanisms to reduce inhibitory inputs to pyramidal neurons in the infragranular layers of the DLPFC.

Project description:Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

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Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia.

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Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia.

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