Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145554 | GEO | 2020/02/20
REPOSITORIES: GEO
Similar Datasets
Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqManM-BM-.-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFM-NM-2) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia. Gene epxression microarray from RNA isolated from pyramidal cells in layer III of the STG from 9 normal controls and 9 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).
2012-05-14 | E-GEOD-37981 | biostudies-arrayexpress
Project description:Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of BrodmannM-bM-^@M-^Ys area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. 739 mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons as found in the accompanying study, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type-specific. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of targeted molecular intervention. Gene expression microarray from mRNA isolated from parvalbumin cells in layer 3 of the STG from 8 normal controls and 8 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).
2013-05-01 | E-GEOD-46509 | biostudies-arrayexpress
Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqMan®-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFβ) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia.
2012-05-15 | GSE37981 | GEO
Project description:Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. 739 mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons as found in the accompanying study, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type-specific. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of targeted molecular intervention.
2013-05-01 | GSE46509 | GEO
Project description:Schizophrenia is a chronic mental illness that is among the world’s top twenty causes of years lost to disability according to the global burden of disease 2019 (10.1016/S0140-6736(20)30925-9). Positive symptoms, including hallucinations and delusions in schizophrenia, often improved with conventional antipsychotic medication, which exerts its therapeutic effects mainly by antagonizing the dopamine D2 receptors. Haloperidol was one of the first antipsychotics to be approved by the FDA, and it is since then widely used for the treatment of psychotic disorders including schizophrenia. Despite its high affinity for dopamine D2 receptors, it has been shown that haloperidol interacts with other receptors, such as dopamine D3 and D4 receptors, α-adrenergic receptor 1 and to some extent 5HT2A. Dopaminergic dysfunction is known for decades to be involved in the pathophysiology of schizophrenia, but only recently has the striatum been implicated in such devasting disorder. The dorsal striatum is a brain region involved in motor, cognitive and motivational functions, highly impacted by antipsychotic drugs. Particularly, it is well-recognized that chronic haloperidol administration has a tremendous impact on striatal synaptic plasticity, by changing the volume of dorsal striatum, the number of striatal neurons and the synaptic morphology, both in humans and rodents. Despite the overwhelming evidence correlating chronic haloperidol administration with striatum alterations, so far, the exact striatal synaptic mechanism by which haloperidol exerts its beneficial effects remains unclear. Although dopamine D2 receptor blockade can be achieved within hours after haloperidol administration, the onset of action is delayed by weeks. Thus, it is crucial to better understand the neuronal mechanism behind the delayed clinical effects of haloperidol to improve the treatment outcome. Using proteomic analysis and whole-cell patch-clamp recordings (Figure 1), we demonstrate for the first time a possible mechanism by which haloperidol may be contributing to its beneficial long-term therapeutic effect. Specifically, we demonstrate that modulation of D2-MSNs by chronic haloperidol administration leads to a slow remodeling of D1-neurons that may be responsible for its positive therapeutic effects.
2023-10-24 | PXD038471 | Pride
Project description:The subcellular localization and translation of messenger RNA (mRNA) supports functional differentiation between cellular compartments. In neuronal dendrites, local translation of mRNA provides a rapid and specific mechanism for synaptic plasticity and memory formation, and might be involved in the pathophysiology of certain brain disorders. Despite the importance of dendritic mRNA translation, little is known about which mRNAs can be translated in dendrites in vivo and when their translation occurs. Here we collect ribosome-bound mRNA from the dendrites of CA1 pyramidal neurons in the adult mouse hippocampus. We find that dendritic mRNA rapidly associates with ribosomes following a novel experience consisting of a contextual fear conditioning trial. High throughput RNA sequencing followed by machine learning classification reveals an unexpected breadth of ribosome-bound dendritic mRNAs, including mRNAs expected to be entirely somatic. Our findings are in agreement with a mechanism of synaptic plasticity that engages the acute local translation of functionally diverse dendritic mRNAs. RNA-Seq of ribosome-bound mRNA immunoprecipitated from dendrites and soma of CA1 pyramidal neurons in the mouse hippocampus
2014-07-30 | E-GEOD-58343 | biostudies-arrayexpress
Project description:Background. Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell, and pharmacological studies suggest an important overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics in medium spiny neurons (MSNs). Methods. We applied single-cell RNA-sequencing to striatal samples from C57BL/6J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We implemented careful statistical analyses to identify differentially expressed genes in two cell populations identified from the single-cell RNA-sequencing (MSNs and microglia) and applied multiple analysis pipelines to contextualize these findings. Results. Differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) in MSNs from mice treated with olanzapine vs. haloperidol. DEGs were enriched in broad loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses highlighted alternative splicing, mitochondrial function, and neuron and synapse development as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. Conclusions. Our goal was to evaluate connections between schizophrenia genetic findings and cellular gene expression changes following antipsychotic exposure. We found that differential gene expression in MSNs from mice chronically treated with olanzapine converges on similar pathways and gene sets.
2021-04-14 | GSE171977 | GEO
Project description:Schizophrenia is a debilitating neurological disorder for which no cure exists. Few defining characteristics of schizophrenic neurons have been identified and the molecular mechanisms responsible for schizophrenia are not well understood, in part due to the lack of patient material for study. Human induced pluripotent stem cells (hiPSCs) offer a new strategy for studying schizophrenia. We have created the first cell-based human model of a complex genetic psychiatric disease by generating hiPSCs from schizophrenic patients and subsequently differentiating these cells to hiPSC-derived neurons in vitro. Schizophrenic hiPSC-derived neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of schizophrenic hiPSC-derived neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the schizophrenic phenotype were ameliorated following treatment of schizophrenic hiPSC-derived neurons with the antipsychotic loxapine. 3 independent differentiations (biological replicates) for each of four control and four schizophrenic patients were analyzed.
2011-05-01 | E-GEOD-25673 | biostudies-arrayexpress
Project description:Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models amenable for studying the neurobiology of schizophrenia may contribute to fill the gaps led by the widely employed animal models. Here we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to resective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass- spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia.
2024-02-06 | PXD046944 | Pride
Project description:The suppression of fear memory in the absence of danger (fear extinction) requires coordinated neural activity within the amygdala and medial prefrontal (prelimbic and infralimbic) cortex. Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear memory and extinction. In the present study, we investigated the effects of optogenetic manipulations of prelimbic pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in fear extinction. To this aim, transgenic mice (Thy1-COP4) having cortical and amygdala pyramidal neurons optogenetically excitable were (or not) fear-conditioned. During the extinction phase, the mice received optogenetic (or sham) stimulations to maintain the activation of the prelimbic pyramidal neurons and impair fear extinction. At the end of behavioral testing, electrophysiological (Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the pyramidal neurons of prelimbic cortex. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Results demonstrate that pyramidal neurons of prelimbic cortex are involved in modulation of the fear responses during extinction phase and their optogenetic stimulation in fear-conditioned mice results in strong modifications of the amygdala transcriptome. Understanding the transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
2021-01-14 | GSE162417 | GEO