scholarly journals Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity

2020 ◽  
Author(s):  
Xiaojun Wu ◽  
Rammohan Shukla ◽  
Khaled Alganem ◽  
Erica Depasquale ◽  
James Reigle ◽  
...  
Keyword(s):  
Differential Expression ◽  
Pyramidal Neurons ◽  
Chronic Schizophrenia ◽  
Gene Set Enrichment Analysis ◽  
Anterior Cingulate ◽  
Postmortem Brain ◽  
Antipsychotic Treatment ◽  
Specific Cell ◽  
Control Subjects ◽  
Differential Expression Gene

AbstractWhile the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed over-represented groups of gene sets in schizophrenia, particularly in immunity and synapse related pathways in pyramidal neurons, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, post-synaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. By comparing our differential expression gene profiles with 51 antipsychotic treatment datasets, we demonstrated that our results were not influenced by antipsychotic treatment of our subjects. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.

Dysfunction of a distributed neural circuitry in schizophrenia patients during a working-memory performance

2005 ◽  
Vol 35 (2) ◽  
pp. 187-196 ◽  
Author(s):  
A. MENDREK ◽  
K. A. KIEHL ◽  
A. M. SMITH ◽  
D. IRWIN ◽  
B. B. FORSTER ◽  
...  
Keyword(s):  
Working Memory ◽  
Memory Performance ◽  
Memory Task ◽  
Anterior Cingulate ◽  
First Episode ◽  
Antipsychotic Treatment ◽  
Compensatory Mechanism ◽  
Control Subjects ◽  
Left Dlpfc ◽  
The Right

Background. In a recent longitudinal study of first-episode schizophrenia patients, we found that while dysfunction of the right dorsolateral prefrontal cortex (DLPFC), right thalamus, left cerebellum and cingulate gyrus normalized with antipsychotic treatment and significant reduction in symptomatology, the left DLPFC, left thalamus, and right cerebellum remained disturbed. In the present study we investigated whether these abnormalities are also present in clinically stable, relatively well-functioning schizophrenia patients in comparison to control subjects during performance of the N-back working-memory task.Method. Twelve schizophrenia and 12 control subjects completed the study. The functional images collected during scanning were analyzed using a random-effects model in a restricted set of six regions of interest (ROIs). In addition, the exploratory search in the entire brain volume was performed.Results. The ROI analyses revealed relative underactivation in the region of the left DLPFC and the right cerebellum, as well as overactivation in the left cerebellum. The exploratory whole-brain search exposed additional overactivation in the medial frontal, anterior cingulate, and left parietal cortices.Conclusions. The present study provides evidence of significant underactivations in stable schizophrenia patients in regions that we have previously observed to be dysfunctional in acutely psychotic and partially remitted patients, together with extensive overactivations in several regions that potentially reflect some compensatory mechanism or increased effort on the working-memory task.

scholarly journals Antipsychotics modulate the expression of the 5’ ecto-nucleotidase NT5E (CD73) in the brains of patients with schizophrenia.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Psychotic Disorders ◽  
Pyramidal Neurons ◽  
Specific Effect ◽  
Microarray Dataset ◽  
Antipsychotic Treatment ◽  
Receptor Subtypes ◽  
Positive Symptoms ◽  
Antipsychotic Medications ◽  
Control Subjects ◽  
Schizophrenic Patients

Antipsychotic medications are used in patients with schizophrenia and related psychotic disorders to control positive symptoms (1, 2). Positive symptoms include hallucinations - seeing or hearing things that are not present, and delusions - fixed false beliefs (3). The use of antipsychotics was fortuitously arrived at in this patient population (4) and though it is understood which receptor subtypes are pharmacologically modulated by these drugs (5, 6, 7) there is still a lack of understanding regarding the specific therapeutic mechanism, at the level of gene expression, by which they exert their function (7, 8, 9). By mining a published microarray dataset (10), we found that the 5’ ecto-nucleotidase NT5E, also known as CD73, was among the genes whose expression was most different in the dorsolateral frontal cortex (DLPFC) of patients with schizophrenia as compared to the DLPFC of control subjects. Analysis of a separate public dataset (11) revealed that schizophrenic patients treated with antipsychotics possessed significantly increased mRNA expression of NT5E in the deep pyramidal neurons when compared to the deep pyramidal neurons of control subjects. This phenomena appeared to be a specific effect of antipsychotic treatment as we could not detect differential expression of NT5E in untreated psychotic patients. These data reveal significantly increased expression of NT5E in the brains of patients with psychotic disorders and suggest that NT5E is a direct target of antipsychotic medications.

scholarly journals Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bastiaan van der Veen ◽  
Sampath K. T. Kapanaiah ◽  
Kasyoka Kilonzo ◽  
Peter Steele-Perkins ◽  
Martin M. Jendryka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Anterior Cingulate Cortex ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Pyramidal Neurons ◽  
Treatment Options ◽  
Pyramidal Cells ◽  
Cingulate Cortex ◽  
Cell Types ◽  
Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

scholarly journals Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity

2021 ◽  
Author(s):  
Xiaojun Wu ◽  
Rammohan Shukla ◽  
Khaled Alganem ◽  
Xiaolu Zhang ◽  
Hunter M. Eby ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Chronic Schizophrenia ◽  
Transcriptional Profile

scholarly journals Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis

2019 ◽  
Vol 50 (13) ◽  
pp. 2182-2193 ◽  
Author(s):  
Kirsten B. Bojesen ◽  
Bjørn H. Ebdrup ◽  
Kasper Jessen ◽  
Anne Sigvard ◽  
Karen Tangmose ◽  
...  
Keyword(s):  
Psychotic Disorders ◽  
Poor Response ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
First Episode ◽  
Antipsychotic Treatment ◽  
Resonance Spectroscopy ◽  
Reference Levels ◽  
Clinical Prognosis ◽  
Episode Psychosis

AbstractBackgroundPoor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).MethodsThirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.ResultsBefore treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.ConclusionGlutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

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