scholarly journals Integrative Analysis Revealed Common Genes, Brain Cell-Type and Pathways Between Stiripentol Targets and Risk Genes of Dravet Syndrome and Epilepsy

2021 ◽  
Author(s):  
Yu-qin Lv ◽  
Yu-zhuang Jiao ◽  
Yan-hua Wang ◽  
Na Wang ◽  
Lei Gao ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Cell Types ◽  
Brain Cell ◽  
Dravet Syndrome ◽  
P Value ◽  
Cell Type ◽  
Risk Genes ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Ca1 ◽  
Brain Cell Types

Abstract Stiripentol is an anti-epileptic drug used for treating Dravet syndrome and epilepsy. To explore common molecular mechanism between antiepileptic effect of stiripentol and genetic etiology of Dravet syndrome and epilepsy, we retrieved target genes of stiripentol through DrugBank database, as well as risk genes of Dravet syndrome and epilepsy from related Database and literature research. Then we performed genetic overlap analysis, Expression Weighted Cell type Enrichment (EWCE) analysis based on single-cell RNA-sequencing (scRNA-seq) data of brain, as well as pathway enrichment analysis. A total of 23, 19 and 118 genes were retrieved for stiripentol targets, risk genes of Dravet syndrome and epilepsy respectively. For stiripentol targets and risk genes of Dravet syndrome, three genes (GABRA1, GABRB3 and GABRG2) were overlapped with P-value of 1.265×10−6; hippocampal CA1 pyramidal cells and interneurons were common brain cell types that were significantly enriched by EWCE; and 10 common pathways were identified. For stiripentol targets and risk genes of epilepsy, five genes (GABRA1, GABRA2, GABRB2, GABRB3, and GABRG2) were overlapped with P-value of 1.963 × 10−7; hippocampal CA1 pyramidal cells and interneurons were also common brain cell types that were significantly enriched and 22 common pathways were identified. Our results revealed that stiripentol might exert its anti-epileptic effect by regulating GABAA receptors on hippocampal CA1 pyramidal cells and interneurons.

Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing

Cephalalgia ◽  
2018 ◽  
Vol 38 (13) ◽  
pp. 1976-1983 ◽  
Author(s):  
William Renthal
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Cell Types ◽  
Susceptibility Genes ◽  
Brain Cell ◽  
Cell Type ◽  
Single Cell Rna Sequencing ◽  
Brain Cell Types

Background Migraine is a debilitating disorder characterized by severe headaches and associated neurological symptoms. A key challenge to understanding migraine has been the cellular complexity of the human brain and the multiple cell types implicated in its pathophysiology. The present study leverages recent advances in single-cell transcriptomics to localize the specific human brain cell types in which putative migraine susceptibility genes are expressed. Methods The cell-type specific expression of both familial and common migraine-associated genes was determined bioinformatically using data from 2,039 individual human brain cells across two published single-cell RNA sequencing datasets. Enrichment of migraine-associated genes was determined for each brain cell type. Results Analysis of single-brain cell RNA sequencing data from five major subtypes of cells in the human cortex (neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells) indicates that over 40% of known migraine-associated genes are enriched in the expression profiles of a specific brain cell type. Further analysis of neuronal migraine-associated genes demonstrated that approximately 70% were significantly enriched in inhibitory neurons and 30% in excitatory neurons. Conclusions This study takes the next step in understanding the human brain cell types in which putative migraine susceptibility genes are expressed. Both familial and common migraine may arise from dysfunction of discrete cell types within the neurovascular unit, and localization of the affected cell type(s) in an individual patient may provide insight into to their susceptibility to migraine.

scholarly journals Genetic identification Of brain cell types underlying schizophrenia

2017 ◽  
Author(s):  
Nathan G. Skene ◽  
Julien Bryois ◽  
Trygve E. Bakken ◽  
Gerome Breen ◽  
James J Crowley ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Cell Types ◽  
Brain Cell ◽  
Common Variant ◽  
Genetic Identification ◽  
Medium Spiny Neurons ◽  
Gene Sets ◽  
The Common ◽  
The Brain ◽  
Brain Cell Types

AbstractWith few exceptions, the marked advances in knowledge about the genetic basis for schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. The common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to distinct sets of genes specifically expressed in each of these cell types. Many of the diverse gene sets associated with schizophrenia (including antipsychotic targets) implicate the same brain cell types. Our results provide a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. While some of the genetic risk is associated with GABAergic interneurons, this risk largely does not overlap with that from projecting cells.

scholarly journals The Entorhinal Cortical Alvear Pathway Differentially Excites Pyramidal Cells and Interneuron Subtypes in Hippocampal CA1

2020 ◽  
Author(s):  
Karen A Bell ◽  
Rayne Delong ◽  
Priyodarshan Goswamee ◽  
A Rory McQuiston
Keyword(s):  
Brain Slices ◽  
Pyramidal Cells ◽  
Excitatory Input ◽  
Theta Burst Stimulation ◽  
Ca1 Pyramidal Cells ◽  
Whole Cell Patch Clamp ◽  
Hippocampal Ca1 ◽  
Physiological Impact ◽  
Theta Burst ◽  
Synaptic Responses

Abstract The entorhinal cortex alvear pathway is a major excitatory input to hippocampal CA1, yet nothing is known about its physiological impact. We investigated the alvear pathway projection and innervation of neurons in CA1 using optogenetics and whole cell patch clamp methods in transgenic mouse brain slices. Using this approach, we show that the medial entorhinal cortical alvear inputs onto CA1 pyramidal cells (PCs) and interneurons with cell bodies located in stratum oriens were monosynaptic, had low release probability, and were mediated by glutamate receptors. Optogenetic theta burst stimulation was unable to elicit suprathreshold activation of CA1 PCs but was capable of activating CA1 interneurons. However, different subtypes of interneurons were not equally affected. Higher burst action potential frequencies were observed in parvalbumin-expressing interneurons relative to vasoactive-intestinal peptide-expressing or a subset of oriens lacunosum-moleculare (O-LM) interneurons. Furthermore, alvear excitatory synaptic responses were observed in greater than 70% of PV and VIP interneurons and less than 20% of O-LM cells. Finally, greater than 50% of theta burst-driven inhibitory postsynaptic current amplitudes in CA1 PCs were inhibited by optogenetic suppression of PV interneurons. Therefore, our data suggest that the alvear pathway primarily affects hippocampal CA1 function through feedforward inhibition of select interneuron subtypes.

Modeling Research on Spatiotemporal Dynamics of the Hippocampus

1997 ◽  
Vol 07 (01) ◽  
pp. 187-198 ◽  
Author(s):  
Haijian Sun ◽  
Lin Liu ◽  
Chunhua Feng ◽  
Aike Guo
Keyword(s):  
Pyramidal Cells ◽  
Behavioral Pattern ◽  
Spatiotemporal Dynamics ◽  
Epileptic Focus ◽  
Power Law Distribution ◽  
Ca1 Pyramidal Cells ◽  
Self Organized ◽  
Hippocampal Ca1 ◽  
Self Organized Criticality ◽  
Neurological Insult

The spatiotemporal dynamics of the hippocampus is studied. We first propose a fractal algorithm to model the growth of hippocampal CA1 pyramidal cells, together with an avalanche model for information transmission. Then the optical records of an epileptic focus in the hippocampus are analyzed and simulated. These processes indicate that the hippocampus normally stays in self-organized criticality with a harmonious spatiotemporal behavioral pattern, that is, showing 1/f fluctuation and power law distribution. In case of a neurological insult, the hippocampal system may step into supercriticality and initiate epilepsy.

Distance-Dependent Ni2+-Sensitivity of Synaptic Plasticity in Apical Dendrites of Hippocampal CA1 Pyramidal Cells

2002 ◽  
Vol 87 (2) ◽  
pp. 1169-1174 ◽  
Author(s):  
Yoshikazu Isomura ◽  
Yoko Fujiwara-Tsukamoto ◽  
Michiko Imanishi ◽  
Atsushi Nambu ◽  
Masahiko Takada
Keyword(s):  
Calcium Influx ◽  
Critical Role ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Apical Dendrite ◽  
Excitatory Postsynaptic Potential ◽  
Distal Dendrite ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Ca1

Low concentration of Ni2+, a T- and R-type voltage-dependent calcium channel (VDCC) blocker, is known to inhibit the induction of long-term potentiation (LTP) in the hippocampal CA1 pyramidal cells. These VDCCs are distributed more abundantly at the distal area of the apical dendrite than at the proximal dendritic area or soma. Therefore we investigated the relationship between the Ni2+-sensitivity of LTP induction and the synaptic location along the apical dendrite. Field potential recordings revealed that 25 μM Ni2+ hardly influenced LTP at the proximal dendritic area (50 μm distant from the somata). In contrast, the same concentration of Ni2+ inhibited the LTP induction mildly at the middle dendritic area (150 μm) and strongly at the distal dendritic area (250 μm). Ni2+ did not significantly affect either the synaptic transmission at the distal dendrite or the burst-firing ability at the soma. However, synaptically evoked population spikes recorded near the somata were slightly reduced by Ni2+ application, probably owing to occlusion of dendritic excitatory postsynaptic potential (EPSP) amplification. Even when the stimulating intensity was strengthened sufficiently to overcome such a reduction in spike generation during LTP induction, the magnitude of distal LTP was not significantly recovered from the Ni2+-dependent inhibition. These results suggest that Ni2+ may inhibit the induction of distal LTP directly by blocking calcium influx through T- and/or R-type VDCCs. The differentially distributed calcium channels may play a critical role in the induction of LTP at dendritic synapses of the hippocampal pyramidal cells.

Zn2+ Blocks the NMDA- and Ca2+-Triggered Postexposure Current I pe in Hippocampal Pyramidal Cells

1998 ◽  
Vol 79 (2) ◽  
pp. 1124-1126 ◽  
Author(s):  
Qiang X. Chen ◽  
Katherine L. Perkins ◽  
Robert K. S. Wong
Keyword(s):  
Divalent Cations ◽  
Pyramidal Cells ◽  
Cell Voltage ◽  
Continuous Growth ◽  
Ca1 Pyramidal Cells ◽  
Cation Current ◽  
Hippocampal Ca1 ◽  
Intracellular Ca ◽  
Hippocampal Pyramidal Cells

Chen, Qiang X., Katherine L. Perkins, and Robert K. S. Wong. Zn2+ blocks the NMDA- and Ca2+-triggered postexposure current I pe in hippocampal pyramidal cells. J. Neurophysiol. 79: 1124–1126, 1998. Whole cell voltage-clamp recordings from acutely isolated hippocampal CA1 pyramidal cells from adult guinea pigs were used to evaluate divalent cations as possible blockers of the postexposure current ( I pe). I pe is a cation current that is triggered by the rise in intracellular Ca2+ concentration that occurs after the application of a toxic level of N-methyl-d-aspartate (NMDA). Once triggered, I pe continues to grow until death of the neuron occurs. I pe may be a critical link between transient NMDA exposure and cell death. I pe was blocked by micromolar concentrations of Zn2+. The Zn2+ effect had an IC50 of 64 μM and saturated at 500 μM. Prolonged Zn2+ block of I pe revealed that the maintenance of a steady I pe is not dependent on I pe-mediated Ca2+ influx but that the continuous growth in I pe is dependent on I pe-mediated Ca2+ influx. The availability of an effective blocker of I pe should facilitate the investigation of the intracellular activation pathway of I pe and the role of I pe in neuronal death.

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