Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

2021 ◽  
pp. 1-10
Author(s):  
Kristen Springer ◽  
Nissi Varghese ◽  
Anastasios V. Tzingounis
Keyword(s):  
Age Of Onset ◽  
Cell Types ◽  
Brain Regions ◽  
Epileptic Activity ◽  
Epileptic Encephalopathy ◽  
Current View ◽  
Great Effort ◽  
Neonatal Seizures ◽  
Developmentally Regulated ◽  
Disease States

KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.

scholarly journals STAB: a spatio-temporal cell atlas of the human brain

2020 ◽  
Vol 49 (D1) ◽  
pp. D1029-D1037
Author(s):  
Liting Song ◽  
Shaojun Pan ◽  
Zichao Zhang ◽  
Longhao Jia ◽  
Wei-Hua Chen ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Temporal Dynamics ◽  
Cell Types ◽  
Brain Regions ◽  
Molecular Characteristics ◽  
Great Effort ◽  
Brain Functions ◽  
Spatio Temporal ◽  
The Brain

Abstract The human brain is the most complex organ consisting of billions of neuronal and non-neuronal cells that are organized into distinct anatomical and functional regions. Elucidating the cellular and transcriptome architecture underlying the brain is crucial for understanding brain functions and brain disorders. Thanks to the single-cell RNA sequencing technologies, it is becoming possible to dissect the cellular compositions of the brain. Although great effort has been made to explore the transcriptome architecture of the human brain, a comprehensive database with dynamic cellular compositions and molecular characteristics of the human brain during the lifespan is still not available. Here, we present STAB (a Spatio-Temporal cell Atlas of the human Brain), a database consists of single-cell transcriptomes across multiple brain regions and developmental periods. Right now, STAB contains single-cell gene expression profiling of 42 cell subtypes across 20 brain regions and 11 developmental periods. With STAB, the landscape of cell types and their regional heterogeneity and temporal dynamics across the human brain can be clearly seen, which can help to understand both the development of the normal human brain and the etiology of neuropsychiatric disorders. STAB is available at http://stab.comp-sysbio.org.

scholarly journals Predictive Factors in the Onset of Epilepsy in Children with Cerebral Palsy

2015 ◽  
Vol 61 (3) ◽  
pp. 200-205
Author(s):  
Todoran Butilă Anamaria ◽  
Sin Anca ◽  
Micheu Cristian ◽  
Csep Katalin ◽  
Voidăzan Septimiu ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Birth Weight ◽  
Age Of Onset ◽  
Cerebral Atrophy ◽  
Fetal Distress ◽  
Epileptic Encephalopathy ◽  
Magnetic Resonance Imaging Examination ◽  
Neonatal Seizures ◽  
Term Infants ◽  
Increased Risk

AbstractObjectives: the aim of the study was to identify predictive risk factors of the development of epilepsy in patients with cerebral palsy (CP).Materials and methods: We performed a bidirectional study in wich 177 patients diagnosed with CP with and without epilepsy have been selected for characteristics and risk factor comparison. We analyzed the history related to pregnancy and birth, gestational age, birth weight, fetal distress, the presence of neonatal convulsion, age of onset for the epilepsy, associated types of seizures, the response to anticonvulsant therapy and brain changes identified by Computer tomography and Magnetic resonance imaging examination.Results: epilepsy was found in 91 (51.4%) patients, most frequently in quadriplegic form (76.2% vs 23.8%), OR:3.04, 95% CI:1.42-6.52, p-0.005. In this group, the most common were partial seizures (34.4%), epileptic encephalopathy like Lennox Gastaut and West type (62.5%), and also neonatal seizures. Eighty percent of on-term infants with neonatal seizures later developed epilepsy. Factors like fetal distress, low birth weight, cytomegalovirus infection, history of pathological pregnancy were associated with an increased risk of developing epilepsy. Imaging change, especially cerebral atrophy had the highest frequency (37.5% vs 16%) in pacients with epilepsy. 28 (30.8%) patients had resistance epilepsy, 13 (46.4%) of them having quadriplegia. Early onset of epilepsy constitutes a sign of severity of epileptic forms (OR:3.09, 95% CI:1.187-8.061, p-0.01).Conclusions: The data are consistent with those in literature but is necessary following this study to clarify and support the assumption on preddictive factors and prognosis of epilepsy in this population.

scholarly journals Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation

2020 ◽  
Vol 6 (3) ◽  
pp. e418
Author(s):  
Annemarie C.S. Knijnenburg ◽  
Joost Nicolai ◽  
Levinus A. Bok ◽  
Akin Bay ◽  
Alexander P.A. Stegmann ◽  
...  
Keyword(s):  
Head Trauma ◽  
De Novo ◽  
Brain Regions ◽  
Epileptic Activity ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Acute Encephalopathy ◽  
Severe Intellectual Disability ◽  
Eeg Abnormalities ◽  
Slow Activity

ObjectiveDe novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy.MethodsThe clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.ResultsWe describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.ConclusionsAcute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.

Synaptic organization of the gustatory NST

1994 ◽  
Vol 52 ◽  
pp. 150-151
Author(s):  
M. C. Whitehead
Keyword(s):  
Central Nervous System ◽  
Dendritic Spines ◽  
Fundamental Problem ◽  
Cell Types ◽  
Brain Regions ◽  
Excitatory Synapses ◽  
Solitary Tract ◽  
Synaptic Organization ◽  
Synaptic Junctions ◽  
Afferent Terminals

A fundamental problem in taste research is to determine how gustatory signals are processed and disseminated in the mammalian central nervous system. An important first step toward understanding information processing is the identification of cell types in the nucleus of the solitary tract (NST) and their synaptic relationships with oral primary afferent terminals. Facial and glossopharyngeal (LIX) terminals in the hamster were labelled with HRP, examined with EM, and characterized as containing moderate concentrations of medium-sized round vesicles, and engaging in asymmetrical synaptic junctions. Ultrastructurally the endings resemble excitatory synapses in other brain regions.Labelled facial afferent endings in the RC subdivision synapse almost exclusively with distal dendrites and dendritic spines of NST cells. Most synaptic relationships between the facial synapses and the dendrites are simple. However, 40% of facial endings engage in complex synaptic relationships within glomeruli containing unlabelled axon endings particularly ones termed "SP" endings. SP endings are densely packed with small, pleomorphic vesicles and synapse with both the facial endings and their postsynaptic dendrites by means of nearly symmetrical junctions.

scholarly journals Differential Effects of Toll-Like Receptor Activation and Differential Mediation by MAP Kinases of Immune Responses in Microglial Cells

2021 ◽  
Author(s):  
Jaedeok Kwon ◽  
Christos Arsenis ◽  
Maria Suessmilch ◽  
Alison McColl ◽  
Jonathan Cavanagh ◽  
...  
Keyword(s):  
Map Kinase ◽  
Microglial Activation ◽  
Map Kinases ◽  
Mrna Level ◽  
Cell Types ◽  
Receptor Activation ◽  
Microglial Cells ◽  
Toll Like Receptor ◽  
Disease States ◽  
Nitrite Production

AbstractMicroglial activation is believed to play a role in many psychiatric and neurodegenerative diseases. Based largely on evidence from other cell types, it is widely thought that MAP kinase (ERK, JNK and p38) signalling pathways contribute strongly to microglial activation following immune stimuli acting on toll-like receptor (TLR) 3 or TLR4. We report here that exposure of SimA9 mouse microglial cell line to immune mimetics stimulating TLR4 (lipopolysaccharide—LPS) or TLR7/8 (resiquimod/R848), results in marked MAP kinase activation, followed by induction of nitric oxide synthase, and various cytokines/chemokines. However, in contrast to TLR4 or TLR7/8 stimulation, very few effects of TLR3 stimulation by poly-inosine/cytidine (polyI:C) were detected. Induction of chemokines/cytokines at the mRNA level by LPS and resiquimod were, in general, only marginally affected by MAP kinase inhibition, and expression of TNF, Ccl2 and Ccl5 mRNAs, along with nitrite production, were enhanced by p38 inhibition in a stimulus-specific manner. Selective JNK inhibition enhanced Ccl2 and Ccl5 release. Many distinct responses to stimulation of TLR4 and TLR7 were observed, with JNK mediating TNF protein induction by the latter but not the former, and suppressing Ccl5 release by the former but not the latter. These data reveal complex modulation by MAP kinases of microglial responses to immune challenge, including a dampening of some responses. They demonstrate that abnormal levels of JNK or p38 signalling in microglial cells will perturb their profile of cytokine and chemokine release, potentially contributing to abnormal inflammatory patterns in CNS disease states.

A ligand-receptor model for the cohesive behaviour of Dictyostelium discoideum axenic cells

1979 ◽  
Vol 37 (1) ◽  
pp. 157-167
Author(s):  
A.R. Jaffe ◽  
A.P. Swan ◽  
D.R. Garrod
Keyword(s):  
Molecular Weight ◽  
Stationary Phase ◽  
Chelating Agent ◽  
Cell Types ◽  
Low Molecular Weight ◽  
Receptor Model ◽  
Phase Growth ◽  
Developmentally Regulated ◽  
Receptor System ◽  
Contact Sites

Axenically grown cells of D. discoideum Ax-2 harvested in the log phase of growth, cohere rapidly when shaken in phosphate buffer. After 3.5 days in the stationary phase of growth, cells become completely non-cohesive. Although they do not stick to each other, stationary phase cells do stick to both log phase cells and aggregation-competent cells. The cohesion of stationary phase cells with these other 2 cell types is inhibited by both EDTA and the low-molecular-weight factor which we have previously demonstrated in stationary-phase growth medium. There is a decline in the sensitivity of slime mould cell cohesion to the low-molecular-weight inhibitory factor as the cells become aggregation-competent. This effect parallels the developmentally-regulated decline in sensitivity to EDTA. The low-molecular-weight inhibitor is not a chelating agent, however. The effect of the inhibitor seems to be specifically against contact sites-B mediated cohesion. We suggest that the simplest cohesive mechanism which can explain our results, is that the EDTA-sensitive cohesion of log phase cells could be dependent on a ligand-receptor system.

A novel H+ permeability dominating intracellular pH in the early mouse embryo

Development ◽  
1993 ◽  
Vol 118 (4) ◽  
pp. 1353-1361
Author(s):  
J.M. Baltz ◽  
J.D. Biggers ◽  
C. Lechene
Keyword(s):  
Plasma Membrane ◽  
Intracellular Ph ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Types ◽  
Preimplantation Embryos ◽  
Developmentally Regulated ◽  
Cell Stage ◽  
K Concentration ◽  
Early Mouse

Most cell types are relatively impermeant to H+ and are able to regulate their intracellular pH by means of plasma membrane proteins, which transport H+ or bicarbonate across the membrane in response to perturbations of intracellular pH. Mouse preimplantation embryos at the 2-cell stage, however, do not appear to possess specific pH-regulatory mechanisms for relieving acidosis. They are, instead, highly permeable to H+, so that the intracellular pH in the acid and neutral range is determined by the electrochemical equilibrium of H+ across the plasma membrane. When intracellular pH is perturbed, the rate of the ensuing H+ flux across the plasma membrane is determined by the H+ electrochemical gradient: its dependence on external K+ concentration indicates probable dependence on membrane potential and the rate depends on the H+ concentration gradient across the membrane. The large permeability at the 2-cell stage is absent or greatly diminished in the trophectoderm of blastocysts, but still present in the inner cell mass. Thus, the permeability to H+ appears to be developmentally regulated.

scholarly journals Single-cell transcriptomic analysis elucidates APOE genotype specific changes across cell types in two brain regions in Alzheimer’s disease

2021 ◽  
Author(s):  
Stella Belonwu ◽  
Yaqiao Li ◽  
Daniel Bunis ◽  
Arjun Arkal Rao ◽  
Caroline Warly Solsberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Apoe Genotype ◽  
Cell Types ◽  
Brain Regions ◽  
Single Cell Level ◽  
Cell Level ◽  
Single Nucleus

Abstract Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. Here, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

scholarly journals Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

2021 ◽  
Vol 15 ◽  
Author(s):  
Louis-Philippe Bernier ◽  
Clément Brunner ◽  
Azzurra Cottarelli ◽  
Matilde Balbi
Keyword(s):  
Brain Function ◽  
Energy Demand ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Brain Regions ◽  
Regional Heterogeneity ◽  
Regional Specialization ◽  
Multiple Cell ◽  
Cellular Components ◽  
The Brain

The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

scholarly journals Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

2021 ◽  
Author(s):  
Wouter van Rheenen ◽  
Rick A.A. van der Spek ◽  
Mark K. Bakker ◽  
Joke J.F.A. van Vugt ◽  
Paul J. Hop ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rare Variants ◽  
Unmet Need ◽  
Life Time ◽  
Cell Types ◽  
Brain Regions ◽  
Multiple Traits ◽  
Association Analyses ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

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