scholarly journals Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's

2021 ◽  
Author(s):  
Viktor Janos Olah ◽  
Annie M Goettemoeller ◽  
Jordane Dimidschstein ◽  
Matthew JM Rowan
Keyword(s):  
Gene Expression ◽  
Genetic Risk ◽  
Cortical Excitability ◽  
Network Activity ◽  
Causal Factors ◽  
K Channels ◽  
Kv Channel ◽  
Early Biomarkers ◽  
Gamma Frequency ◽  
Prodromal Ad

In Alzheimer's disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD. Here we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency specific network hyperexcitability. Our findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.

scholarly journals Acute Oxygen Sensing in Heme Oxygenase-2 Null Mice

2006 ◽  
Vol 128 (4) ◽  
pp. 405-411 ◽  
Author(s):  
Patricia Ortega-Sáenz ◽  
Alberto Pascual ◽  
Raquel Gómez-Díaz ◽  
José López-Barneo
Keyword(s):  
Gene Expression ◽  
K Channel ◽  
Α Subunit ◽  
Organ Growth ◽  
K Channels ◽  
Channel Gene ◽  
Sensitive Organ ◽  
Stress Dependent ◽  
Acute Oxygen Sensing ◽  
O2 Sensing

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K+ channels and has been proposed to be the acute O2 sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O2 sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K+ channel α-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K+ channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O2-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K+ channel gene expression but it does not alter the intrinsic O2 sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O2 sensor.

Poster #108 ALTERED LANGUAGE NETWORK ACTIVITY IN YOUNG PEOPLE AT GENETIC RISK FOR SCHIZOPHRENIA

2012 ◽  
Vol 136 ◽  
pp. S130
Author(s):  
Lynn E. Pelisi ◽  
Heidi W. Thermenos ◽  
Larry J. Seidman ◽  
Susan Whitfielf-Gabrieli ◽  
Richard Juelich ◽  
...  
Keyword(s):  
Young People ◽  
Genetic Risk ◽  
Network Activity ◽  
Language Network

scholarly journals Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1397-1397
Author(s):  
Diego Chacon ◽  
Ali Braytee ◽  
Yizhou Huang ◽  
Julie Thoms ◽  
Shruthi Subramanian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
High Fidelity ◽  
Improve Outcome ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

scholarly journals Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

2021 ◽  
Author(s):  
Alison G Costigan ◽  
Katja Umla-Runge ◽  
C John Evans ◽  
Rachel Raybould ◽  
Kim S Graham ◽  
...  
Keyword(s):  
Resting State ◽  
Genetic Risk ◽  
Occipital Cortex ◽  
Network Activity ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Gaba A ◽  
Spatio Temporal ◽  
E4 Allele

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ~20-30 have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN) which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, nor in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Results suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or indeed may precede, alterations in local resting-state PMC neurotransmitters, thus informing the spatio-temporal order and the cause/effect dynamic of neuroimaging differences in APOE E4 carriers.

The role of K-channels in the formation of a nociceptive signal in the rat trigeminal nerve

2021 ◽  
Author(s):  
A.D. Buglinina ◽  
T.M. Verkhoturova ◽  
O.Sh. Gafurov ◽  
K.S. Koroleva ◽  
G.F. Sitdikova
Keyword(s):  
Key Words ◽  
Trigeminal Nerve ◽  
Key Words Migraine ◽  
K Channels ◽  
Kv Channel ◽  
Inflammatory Agent ◽  
Kv Channels ◽  
Pain Signal ◽  
Isolated Rat

The central problem of this work is to elucidate the mechanisms of pain in migraine and to establish the role of Kv channels in regulating the excitability of meningeal afferents of the trigeminal nerve that form a pain signal in migraine. The study was conducted on a preparation of an isolated rat skull. It was found that Kv-channel inhibitors 4-aminopyridine (100 microns and 1 mM) and tetraethylammonium (5mm) lead to an increase in the excitability of trigeminal nerve afferents, at the same time, this effect was partially removed by a nonsteroidal anti–inflammatory agent - naproxen, and was not sensitive to sumatriptan, a classic anti-migraine drug. Key words: migraine, K-channels, trigeminal nerve, 4-aminopyridine, tetraethylammonium, naproxen, sumatriptan.

Mechanisms involved in neuroprotective effects of transcranial magnetic stimulation

2021 ◽  
Vol 20 ◽  
Author(s):  
Javier Caballero-Villarraso ◽  
Francisco Javier Medina ◽  
Begoña M. Escribano ◽  
Eduardo Agüera ◽  
Abel Santamaría ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Cortical Excitability ◽  
Therapeutic Effects ◽  
Special Role ◽  
Gamma Aminobutyric Acid ◽  
Neuroprotective Effects ◽  
Paradoxical Response ◽  
Molecular Events

: Transcranial magnetic stimulation (TMS) is widely used in neurophysiology to study cortical excitability. Research over the last few decades has highlighted its additional value as a potential therapeutic tool in the treatment of a broad range of psychiatric disorders. More recently, a number of studies have reported beneficial and therapeutic effects for TMS in neurodegenerative conditions and strokes. Yet despite its recognised clinical applications and despite considerable research using animal models, the molecular and physiological mechanisms through which TMS exerts its beneficial and therapeutic effects remain unclear. They are thought to involve biochemical-molecular events affecting membrane potential and gene expression. In this aspect, the dopaminergic system plays a special role. This is the most directly and selectively modulated neurotransmitter system, producing an increase in the flux of dopamine (DA) in various areas of the brain after the application of repetitive TMS (rTMS). Other neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA) have shown a paradoxical response to rTMS. In this way, their levels increased in the hippocampus and striatum but decreased in the hypothalamus and remained unchanged in the mesencephalon. Similarly, there are sufficient evidences that TMS up-regulates the gene expression of BDNF (one of the main brain neurotrophins). Something similar occurs with the expression of genes such as c-Fos and zif268 that encode trophic and regenerative action neuropeptides. Consequently, the application of TMS can promote the release of molecules involved in neuronal genesis and maintenance. This capacity may mean that TMS becomes a useful therapeutic resource to antagonize processes that underlie the previously mentioned neurodegenerative conditions.

Quantitative neurogenetics: applications in understanding disease

2021 ◽  
Author(s):  
Ali Afrasiabi ◽  
Jeremy T. Keane ◽  
Julian Ik-Tsen Heng ◽  
Elizabeth E. Palmer ◽  
Nigel H. Lovell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Risk ◽  
Tissue Specificity ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Brain Dysfunction ◽  
Neural Cells ◽  
Expression Index ◽  
The Central Nervous System ◽  
The Brain

Neurodevelopmental and neurodegenerative disorders (NNDs) are a group of conditions with a broad range of core and co-morbidities, associated with dysfunction of the central nervous system. Improvements in high throughput sequencing have led to the detection of putative risk genetic loci for NNDs, however, quantitative neurogenetic approaches need to be further developed in order to establish causality and underlying molecular genetic mechanisms of pathogenesis. Here, we discuss an approach for prioritizing the contribution of genetic risk loci to complex-NND pathogenesis by estimating the possible impacts of these loci on gene regulation. Furthermore, we highlight the use of a tissue-specificity gene expression index and the application of artificial intelligence (AI) to improve the interpretation of the role of genetic risk elements in NND pathogenesis. Given that NND symptoms are associated with brain dysfunction, risk loci with direct, causative actions would comprise genes with essential functions in neural cells that are highly expressed in the brain. Indeed, NND risk genes implicated in brain dysfunction are disproportionately enriched in the brain compared with other tissues, which we refer to as brain-specific expressed genes. In addition, the tissue-specificity gene expression index can be used as a handle to identify non-brain contexts that are involved in NND pathogenesis. Lastly, we discuss how using an AI approach provides the opportunity to integrate the biological impacts of risk loci to identify those putative combinations of causative relationships through which genetic factors contribute to NND pathogenesis.

Abstract TP142: Post-Ischemic Cortical Excitability and Gene Expression are Modulated by Transplanted Human Neural Stem Cells

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Ricardo L Azevedo-Pereira ◽  
Tanya Weerakkody ◽  
Jennifer Vu ◽  
Fang Du ◽  
Xibin Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Cortical Excitability ◽  
Human Neural Stem Cells

scholarly journals Can We Assume the Gene Expression Profile as a Proxy for Signaling Network Activity?

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 850 ◽  
Author(s):  
Mehran Piran ◽  
Reza Karbalaei ◽  
Mehrdad Piran ◽  
Jehad Aldahdooh ◽  
Mehdi Mirzaie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Differentially Expressed Genes ◽  
Expression Profile ◽  
Signaling Network ◽  
Differentially Expressed ◽  
Network Activity ◽  
Gene Products ◽  
Expression Data ◽  
Gene Pairs

Studying relationships among gene products by expression profile analysis is a common approach in systems biology. Many studies have generalized the outcomes to the different levels of central dogma information flow and assumed a correlation of transcript and protein expression levels. However, the relation between the various types of interaction (i.e., activation and inhibition) of gene products to their expression profiles has not been widely studied. In fact, looking for any perturbation according to differentially expressed genes is the common approach, while analyzing the effects of altered expression on the activity of signaling pathways is often ignored. In this study, we examine whether significant changes in gene expression necessarily lead to dysregulated signaling pathways. Using four commonly used and comprehensive databases, we extracted all relevant gene expression data and all relationships among directly linked gene pairs. We aimed to evaluate the ratio of coherency or sign consistency between the expression level as well as the causal relationships among the gene pairs. Through a comparison with random unconnected gene pairs, we illustrate that the signaling network is incoherent, and inconsistent with the recorded expression profile. Finally, we demonstrate that, to infer perturbed signaling pathways, we need to consider the type of relationships in addition to gene-product expression data, especially at the transcript level. We assert that identifying enriched biological processes via differentially expressed genes is limited when attempting to infer dysregulated pathways.

Quantitative Gene Expression Analysis of Surrogate Markers for Genetic Risk Groups and Survival in CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4170-4170
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Dirk Winkler ◽  
Manfred Hensel ◽  
Riccardo Dalla-Favera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Survival Analysis ◽  
Genetic Risk ◽  
Proportional Hazards ◽  
Risk Groups ◽  
Cox Proportional Hazards ◽  
Surrogate Markers ◽  
Mutation Status ◽  
Binet Stage

Abstract In CLL, a variety of surrogate markers for individual genetic features, mostly the VH mutation status, were proposed from gene expression analyses. However, their detailed relation to specific genetic subsets such as V3-21 usage, del11q22-q23 (11q−), and del17p13 (17p−), and their prognostic value in relation to established factors is not elucidated yet. Gene expression markers (ADAM29, ATM, CLLU1, DMD, GLO1, HS1, KIAA0977, LPL, MGC9913, PCDH9, PEG10, SEPT10, TCF7, TP53, Vimentin, ZAP-70, ZNF2) were evaluated using real-time quantitative RT-PCR (RQ-PCR) in purified samples of 151 patients. VH sequencing and FISH screening for genomic aberrations were carried out for all cases, survival information was available for 133 cases. Logistic regression was performed to test the predictive value of gene expression for genetic risk groups, Cox proportional hazards statistics for survival analysis. VH mutation status was best assigned by LPL and ZAP70, followed by TCF7, a marker with a characteristic overexpression in VH mutated CLL patients (correct VH prediction in 83%, 83%, and 75% of the patients, respectively). A similar rate of correct VH assignments was achieved in the subgroup of patients with 11q− or 17p− when using these markers (88%, 86%, and 79%, respectively). In contrast to LPL and TCF7, most of the patients with V3-21 usage were recognized as risk patients by ZAP70 independently of the VH status. Therefore, ZAP70 yielded the best results for the overall recognition of patients with a genetic risk constellation (VH unmutated or V3-21 usage or 11q− or 17p−). Comparison of ZAP-70 determination by RQPCR and flow cytometry was performed for 72 patients and revealed 30% of discordant cases. Thereof, the majority was VH unmutated (including several cases with 11q− or 17p−) showing ZAP-70 negativity by FACS and positivity by RQ-PCR. In multivariate analysis of time to first treatment (TFT), ADAM29 was an independent prognostic factor besides the VH status and Binet stage. In overall survival analysis including the gene expression variables only, LPL was the strongest predictor for overall survival. When genetic and clinical factors were added to this analysis, V3-21 usage, 17p−, age, binet stage, and expression of ATM, ADAM29, SEPT10, and TCL1 were identified as significant prognostic factors. In conclusion, novel gene expression markers allow screening for patients at risk but can not fully substitute for the genetic factors, which should therefore at present remain the basis for risk stratification approaches. Some of the novel markers appear to have a prognostic relevance independently of the established factors, which points to relevant biologic and clinical implications demanding further investigation.

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