Phenotypic analysis of catastrophic childhood epilepsy genes

AbstractGenetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

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Phenotypic analysis of catastrophic childhood epilepsy genes: The Epilepsy Zebrafish Project

10.1101/2021.02.11.430844 ◽

2021 ◽

Author(s):

Aliesha Griffin ◽

Colleen Carpenter ◽

Jing Liu ◽

Rosalia Paterno ◽

Brian Grone ◽

...

Keyword(s):

Neurological Disorders ◽

Classification Scheme ◽

Single Gene ◽

Field Potential ◽

Phenotypic Analysis ◽

Electrographic Seizure ◽

Starting Point ◽

Gene Mutant ◽

Epilepsy Classification ◽

Neuroscience Community

AbstractGenetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. A unifying epilepsy classification scheme was developed based on local field potential recordings and blinded scoring from ~3300 larvae. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

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A Role for Gαz in regulating seizure susceptibility

10.1101/567628 ◽

2019 ◽

Author(s):

Rainbo Hultman ◽

Okechi Boms ◽

Stephen Mague ◽

Dalton Hughes ◽

Victor Nadler ◽

...

Keyword(s):

Cortical Neurons ◽

Molecular Mechanisms ◽

Seizure Activity ◽

Dorsal Hippocampus ◽

Field Potential ◽

Brain Regions ◽

Seizure Susceptibility ◽

Electrographic Seizure ◽

Pilocarpine Model ◽

Local Field Potential Lfp

AbstractMuch about the molecular mechanisms underlying seizure susceptibility remains unknown. A number of studies have indicated that the neurotrophic factor BDNF plays an important role in mediating seizure susceptibility. Recently, we found that the heterotrimeric G – protein, Gz, which is known to endogenously couple to monoaminergic receptors, such as serotonin, norepinephrine and dopamine receptors, regulates BDNF-induced signaling and development in cortical neurons. Interestingly, several of the receptors that Gz endogenously couples to have also been shown to be associated with seizure phenotypes (5HT1A-serotonin and D2 dopamine). Here we characterized seizure susceptibility in Gz-null mice, behaviorally and electrographically, finding that Gz-null mice have increased seizure susceptibility using a modified version of the pilocarpine model of status epilepticus. Local field potential (LFP) data recorded from six brain regions-amygdala, dorsal hippocampus, ventral hippocampus, motor cortex, somatosensory cortex, and thalamus-showed robust electrographic seizure activity for Gz-null mice compared with low or no seizure activity in wild-type controls.

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Fields Connected with Particles in Terms of Complex-Riemannian Geometry

Zeitschrift für Naturforschung A ◽

10.1515/zna-1990-0201 ◽

1990 ◽

Vol 45 (2) ◽

pp. 81-94

Author(s):

Julian Ławrynowicz ◽

Katarzyna Kędzia ◽

Leszek Wojtczak

Keyword(s):

Field Potential ◽

Riemannian Metrics ◽

Interaction Matrix ◽

Explicit Calculation ◽

Maxwell System ◽

Curved Space ◽

Starting Point ◽

Autocorrelation Time ◽

The Fourier Transform ◽

Convolution Equations

AbstractA complex analytical method of solving the generalised Dirac-Maxwell system has recently been proposed by two of us for a certain class of complex Riemannian metrics. The Dirac equation without the field potential in such a metric appeared to be equivalent to the Dirac-Maxwell system including the field potentials produced by the currents of a particle in question. The method proposed is connected with applying the Fourier transform with respect to the electric charge treated as a variable, with the consideration of the mass as an eigenvalue, and with solving suitable convolution equations. In the present research an explicit calculation based on linearization of the spinor connections is given. The conditions for the motion are interpreted as a starting point to seek selection rules for curved space-times corresponding to actually existing particles. Then the same method is applied to solids. Namely, by a suitable transformation of the configuration space in terms of elements of the interaction matrix corresponding to the Coulomb, exchange, and dipole integrals, the interaction term in the hamiltonian becomes zero, thus leading to experimentally verificable formulae for the autocorrelation time

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Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2014.16.1/ffroehlich ◽

2014 ◽

Vol 16 (1) ◽

pp. 93-102 ◽

Cited By ~ 15

Keyword(s):

Electric Fields ◽

Brain Stimulation ◽

Rational Design ◽

Brain Activity ◽

Field Potential ◽

Alternating Current ◽

Noninvasive Brain Stimulation ◽

Starting Point ◽

Recent Developments ◽

Transcranial Alternating Current Stimulation

Synchronized neuronal activity in the cortex generates weak electric fields that are routinely measured in humans and animal models by electroencephalography and local field potential recordings. Traditionally, these endogenous electric fields have been considered to be an epiphenomenon of brain activity. Recent work has demonstrated that active cortical networks are surprisingly susceptible to weak perturbations of the membrane voltage of a large number of neurons by electric fields. Simultaneously, noninvasive brain stimulation with weak, exogenous electric fields (transcranial current stimulation, TCS) has undergone a renaissance due to the broad scope of its possible applications in modulating brain activity for cognitive enhancement and treatment of brain disorders. This review aims to interface the recent developments in the study of both endogenous and exogenous electric fields, with a particular focus on rhythmic stimulation for the modulation of cortical oscillations. The main goal is to provide a starting point for the use of rational design for the development of novel mechanism-based TCS therapeutics based on transcranial alternating current stimulation, for the treatment of psychiatric illnesses.

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Flunarizine as a Supplementary Medication in Refractory Childhood Epilepsy: A Double-Blind Crossover Study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100028882 ◽

1989 ◽

Vol 16 (2) ◽

pp. 191-193 ◽

Cited By ~ 16

Author(s):

D. Keene ◽

S. Whiting ◽

P. Humphreys ◽

P. Jacob

Keyword(s):

Seizure Control ◽

Seizure Activity ◽

Childhood Epilepsy ◽

Partial Seizures ◽

Double Blind ◽

Significant Difference ◽

Placebo Phase ◽

Double Blinded ◽

Blind Crossover Study ◽

Double Blind Crossover Study

ABSTRACT:We report a double blinded cross-over study involving Flunarizine versus placebo in the treatment of refractory childhood epilepsy. The patients studied were between the ages of 2 and 18; and were having more than 4 seizures per month not responsive to regular anticonvulsant medications. Of the 34 patients treated, 8 had a 50% decrease in their seizures during the placebo phase, 5 had a 50% decrease during the Flunarizine phase, and 1 patient had a 50% increase in seizures while taking Flunarizine. The remaining 25 patients showed no change in seizure activity in either phase. Patients having partial seizures with secondary generalization tended to do better on Flunarizine than those with other seizure types. Monitoring serum Flunarizine levels showed no significant difference between patients having improved seizure control and those who were unimproved. No significant side effects were noted with this medication, nor were any significant drug interactions noted.

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Ontogenetic study of the fusion of floral organs in the normal and "solanifolia" mutant of tomato (Lycopersicon esculentum)

Canadian Journal of Botany ◽

10.1139/b87-030 ◽

1987 ◽

Vol 65 (2) ◽

pp. 215-221 ◽

Cited By ~ 5

Author(s):

K. N. Chandra Sekhar ◽

V. K. Sawhney

Keyword(s):

Lycopersicon Esculentum ◽

Single Gene ◽

Corolla Tube ◽

Lateral Growth ◽

Floral Organs ◽

Lack Of Fusion ◽

Organ Type ◽

Gene Mutant ◽

Ontogenetic Study ◽

Single Ovary

A comparative study on the ontogeny of the fusion of floral organs of the normal (cv. Pearson) and a single-gene mutant, "solanifolia" (sf/sf), of tomato (Lycopersicon esculentum Mill.) was conducted. In the normal, floral organs were laterally fused, although the degree and the region of fusion varied in each organ type. In the mutant, the various organs either did not fuse or, if they did, were individually recognizable. The sepals and petals of mutant flowers, unlike those of the normal, did not form a calyx cup and a corolla tube, respectively, and this was related to the limited lateral growth of mutant primordia and the absence of growth in the interprimordial region. Also, petal primordia of the mutant were narrower in width at inception. The stamens of normal flowers were fused by interweaving rows of lateral and adaxial hairs on the anthers. The mutant stamens produced lateral and adaxial hairs, yet they were free. The nonfusion of mutant stamens was related to the smaller primordium widths, greater distance between the primordia, and the larger apex diameter at the time of stamen initiation. The gynoecium of normal flowers consisted of a single ovary, style, and stigma formed by the fusion of carpel primordia. In the mutant, the gynoecium consisted of several carpels, laterally adhered to each other, and each had a recognizable style and stigma. The lack of fusion of mutant carpels was attributed to the larger apex diameter of the mutant during carpel initiation.

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Dynamic causal modelling of electrographic seizure activity using Bayesian belief updating

NeuroImage ◽

10.1016/j.neuroimage.2015.07.063 ◽

2016 ◽

Vol 125 ◽

pp. 1142-1154 ◽

Cited By ~ 26

Author(s):

Gerald K. Cooray ◽

Biswa Sengupta ◽

Pamela K. Douglas ◽

Karl Friston

Keyword(s):

Seizure Activity ◽

Belief Updating ◽

Electrographic Seizure ◽

Causal Modelling ◽

Dynamic Causal Modelling

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Comprehensive phenotypic analysis of single-gene deletion and overexpression strains of Saccharomyces cerevisiae

Yeast ◽

10.1002/yea.1843 ◽

2011 ◽

Vol 28 (5) ◽

pp. 349-361 ◽

Cited By ~ 74

Author(s):

Katsunori Yoshikawa ◽

Tadamasa Tanaka ◽

Yoshihiro Ida ◽

Chikara Furusawa ◽

Takashi Hirasawa ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Gene Deletion ◽

Single Gene ◽

Phenotypic Analysis ◽

Single Gene Deletion

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EEG Suppression Associated with Apneic Episodes in a Neonate

Case Reports in Neurological Medicine ◽

10.1155/2012/250801 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Evonne Low ◽

Eugene M. Dempsey ◽

C. Anthony Ryan ◽

Janet M. Rennie ◽

Geraldine B. Boylan

Keyword(s):

Heart Rate ◽

Oxygen Saturation ◽

Preterm Neonate ◽

Seizure Activity ◽

Baseline Heart Rate ◽

Eeg Monitoring ◽

Oxygen Saturation Level ◽

Electrographic Seizure ◽

Eeg Activity ◽

Equivalent Age

We describe the EEG findings from an ex-preterm neonate at term equivalent age who presented with intermittent but prolonged apneic episodes which were presumed to be seizures. A total of 8 apneic episodes were captured (duration 23–376 seconds) during EEG monitoring. The baseline EEG activity was appropriate for corrected gestational age and no electrographic seizure activity was recorded. The average baseline heart rate was 168 beats per minute (bpm) and the baseline oxygen saturation level was in the mid-nineties. Periods of complete EEG suppression lasting 68 and 179 seconds, respectively, were recorded during 2 of these 8 apneic episodes. Both episodes were accompanied by bradycardia less than 70 bpm and oxygen saturation levels of less than 20%. Short but severe episodes of apnea can cause complete EEG suppression in the neonate.

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