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Intrinsic functional architecture of the non-human primate spinal cord derived from fMRI and electrophysiology.
Wu TL, Yang PF, Wang F, Shi Z, Mishra A, Wu R, Chen LM, Gore JC
(2019) Nat Commun 10: 1416
MeSH Terms: Action Potentials, Animals, Electrophysiological Phenomena, Haplorhini, Humans, Magnetic Resonance Imaging, Physical Stimulation, Reproducibility of Results, Rest, Spinal Cord, Spinal Cord Dorsal Horn, Touch
Show Abstract · Added July 11, 2019
Resting-state functional MRI (rsfMRI) has recently revealed correlated signals in the spinal cord horns of monkeys and humans. However, the interpretation of these rsfMRI correlations as indicators of functional connectivity in the spinal cord remains unclear. Here, we recorded stimulus-evoked and spontaneous spiking activity and local field potentials (LFPs) from monkey spinal cord in order to validate fMRI measures. We found that both BOLD and electrophysiological signals elicited by tactile stimulation co-localized to the ipsilateral dorsal horn. Temporal profiles of stimulus-evoked BOLD signals covaried with LFP and multiunit spiking in a similar way to those observed in the brain. Functional connectivity of dorsal horns exhibited a U-shaped profile along the dorsal-intermediate-ventral axis. Overall, these results suggest that there is an intrinsic functional architecture within the gray matter of a single spinal segment, and that rsfMRI signals at high field directly reflect this underlying spontaneous neuronal activity.
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Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.
Musial TF, Molina-Campos E, Bean LA, Ybarra N, Borenstein R, Russo ML, Buss EW, Justus D, Neuman KM, Ayala GD, Mullen SA, Voskobiynyk Y, Tulisiak CT, Fels JA, Corbett NJ, Carballo G, Kennedy CD, Popovic J, Ramos-Franco J, Fill M, Pergande MR, Borgia JA, Corbett GT, Pahan K, Han Y, Chetkovich DM, Vassar RJ, Byrne RW, Matthew Oh M, Stoub TR, Remy S, Disterhoft JF, Nicholson DA
(2018) Neurobiol Learn Mem 154: 141-157
MeSH Terms: Action Potentials, Aging, Alzheimer Disease, Animals, CA1 Region, Hippocampal, Channelopathies, Disease Models, Animal, Endoplasmic Reticulum, Female, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Mice, Transgenic, Neuronal Plasticity, Pyramidal Cells
Show Abstract · Added April 2, 2019
Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.
Copyright © 2018. Published by Elsevier Inc.
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14 MeSH Terms
Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.
Grouthier V, Lebrun-Vignes B, Glazer AM, Touraine P, Funck-Brentano C, Pariente A, Courtillot C, Bachelot A, Roden DM, Moslehi JJ, Salem JE
(2018) Heart 104: 1859-1863
MeSH Terms: Action Potentials, Adolescent, Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aromatase Inhibitors, Cardiotoxicity, Databases, Factual, Europe, Female, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, Middle Aged, Prognosis, Risk Assessment, Risk Factors, Selective Estrogen Receptor Modulators, Tamoxifen, Torsades de Pointes, Young Adult
Show Abstract · Added October 1, 2018
OBJECTIVE - A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.
METHODS - We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.
RESULTS - SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.
CONCLUSIONS - SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.
TRIAL REGISTRATION NUMBER - NCT03259711.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels.
Zobeiri M, Chaudhary R, Datunashvili M, Heuermann RJ, Lüttjohann A, Narayanan V, Balfanz S, Meuth P, Chetkovich DM, Pape HC, Baumann A, van Luijtelaar G, Budde T
(2018) Brain Struct Funct 223: 1537-1564
MeSH Terms: Action Potentials, Adenine, Adenylyl Cyclase Inhibitors, Animals, Cardiovascular Agents, Cerebral Cortex, Cyclic AMP, Cyclic GMP, Female, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neural Pathways, Peroxins, Pyrimidines, Sodium Channel Blockers, Tetrodotoxin, Thalamus, Thionucleotides
Show Abstract · Added April 2, 2019
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I , in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K current, I , in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.
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Overexpressing wild-type γ2 subunits rescued the seizure phenotype in Gabrg2 Dravet syndrome mice.
Huang X, Zhou C, Tian M, Kang JQ, Shen W, Verdier K, Pimenta A, MacDonald RL
(2017) Epilepsia 58: 1451-1461
MeSH Terms: Action Potentials, Animals, Convulsants, Electric Stimulation, Epilepsies, Myoclonic, Humans, In Vitro Techniques, Inhibitory Postsynaptic Potentials, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neural Pathways, Patch-Clamp Techniques, Pentylenetetrazole, Protein Subunits, Pyramidal Cells, Receptors, GABA-A, Somatosensory Cortex, Thalamus
Show Abstract · Added June 21, 2017
OBJECTIVE - The mutant γ-aminobutyric acid type A (GABA ) receptor γ2(Q390X) subunit (Q351X in the mature peptide) has been associated with the epileptic encephalopathy, Dravet syndrome, and the epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+). The mutation generates a premature stop codon that results in translation of a stable truncated and misfolded γ2 subunit that accumulates in neurons, forms intracellular aggregates, disrupts incorporation of γ2 subunits into GABA receptors, and affects trafficking of partnering α and β subunits. Heterozygous Gabrg2 knock-in (KI) mice had reduced cortical inhibition, spike wave discharges on electroencephalography (EEG), a lower seizure threshold to the convulsant drug pentylenetetrazol (PTZ), and spontaneous generalized tonic-clonic seizures. In this proof-of-principal study, we attempted to rescue these deficits in KI mice using a γ2 subunit gene (GABRG2) replacement therapy.
METHODS - We introduced the GABRG2 allele by crossing Gabrg2 KI mice with bacterial artificial chromosome (BAC) transgenic mice overexpressing HA (hemagglutinin)-tagged human γ2 subunits, and compared GABA receptor subunit expression by Western blot and immunohistochemical staining, seizure threshold by monitoring mouse behavior after PTZ-injection, and thalamocortical inhibition and network oscillation by slice recording.
RESULTS - Compared to KI mice, adult mice carrying both mutant allele and transgene had increased wild-type γ2 and partnering α1 and β2/3 subunits, increased miniature inhibitory postsynaptic current (mIPSC) amplitudes recorded from layer VI cortical neurons, reduced thalamocortical network oscillations, and higher PTZ seizure threshold.
SIGNIFICANCE - Based on these results we suggest that seizures in a genetic epilepsy syndrome caused by epilepsy mutant γ2(Q390X) subunits with dominant negative effects could be rescued potentially by overexpression of wild-type γ2 subunits.
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.
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Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome.
Anderson LL, Hawkins NA, Thompson CH, Kearney JA, George AL
(2017) Sci Rep 7: 1682
MeSH Terms: Action Potentials, Animals, Epilepsies, Myoclonic, Ion Channel Gating, Mice, Inbred C57BL, Mice, Knockout, NAV1.1 Voltage-Gated Sodium Channel, NAV1.6 Voltage-Gated Sodium Channel, Neurons, Pyramidal Cells, Pyridines, Seizures, Survival Analysis, Triazoles
Show Abstract · Added October 2, 2018
Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a ) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal Na1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal Na1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in Na1.6.
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Azithromycin Causes a Novel Proarrhythmic Syndrome.
Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, Milne G, Tucker P, George AL, Campbell CM, Pickett RA, Shaffer CM, Chopra N, Yang T, Knollmann BC, Roden DM, Murray KT
(2017) Circ Arrhythm Electrophysiol 10:
MeSH Terms: Action Potentials, Animals, Anti-Bacterial Agents, Arrhythmias, Cardiac, Azithromycin, CHO Cells, Calcium Channel Blockers, Calcium Channels, L-Type, Cricetulus, Dose-Response Relationship, Drug, Electrocardiography, Ambulatory, Female, HEK293 Cells, Heart Rate, Humans, KCNQ1 Potassium Channel, Mice, Inbred C57BL, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Potassium Channels, Voltage-Gated, Rabbits, Sodium Channel Blockers, Telemetry, Time Factors, Transfection, Young Adult
Show Abstract · Added July 6, 2017
BACKGROUND - The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.
METHODS AND RESULTS - In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC=110±3 μmol/L) and Na current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for I in cardiomyocytes. Mild block occurred for K currents representing I (CHO cells expressing hERG; IC=219±21 μmol/L) and I (CHO cells expressing KCNQ1+KCNE1; IC=184±12 μmol/L), whereas azithromycin suppressed L-type Ca currents (rabbit ventricular myocytes, IC=66.5±4 μmol/L) and I (HEK cells expressing Kir2.1, IC=44±3 μmol/L).
CONCLUSIONS - Chronic exposure to azithromycin increases cardiac Na current to promote intracellular Na loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.
© 2017 American Heart Association, Inc.
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Mutant IDH1 and seizures in patients with glioma.
Chen H, Judkins J, Thomas C, Wu M, Khoury L, Benjamin CG, Pacione D, Golfinos JG, Kumthekar P, Ghamsari F, Chen L, Lein P, Chetkovich DM, Snuderl M, Horbinski C
(2017) Neurology 88: 1805-1813
MeSH Terms: Action Potentials, Animals, Brain Neoplasms, Cells, Cultured, Cerebral Cortex, Chromosome Deletion, Chromosomes, Human, Pair 1, Female, Glioma, Glutarates, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Neoplasm Grading, Neurons, Rats, Sprague-Dawley, Retrospective Studies, Seizures
Show Abstract · Added April 2, 2019
OBJECTIVE - Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1 increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.
METHODS - Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1 status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.
RESULTS - Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1) patients and in 59%-74% of IDH1 patients ( < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1 was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.
CONCLUSIONS - The D2HG product of IDH1 may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1 gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1 inhibitors may improve antiepileptic therapy in patients with IDH1 gliomas.
© 2017 American Academy of Neurology.
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M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.
Lv X, Dickerson JW, Rook JM, Lindsley CW, Conn PJ, Xiang Z
(2017) Neuropharmacology 118: 209-222
MeSH Terms: Acetylcholine, Action Potentials, Animals, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Corpus Striatum, Cues, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Female, Gene Expression Regulation, Learning, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Photic Stimulation, Receptor, Muscarinic M1
Show Abstract · Added April 6, 2017
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
Copyright © 2017. Published by Elsevier Ltd.
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mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks.
Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AFT, Paspalas CD
(2018) Cereb Cortex 28: 974-987
MeSH Terms: Action Potentials, Animals, Dose-Response Relationship, Drug, Excitatory Amino Acid Agents, Eye Movements, Female, Image Processing, Computer-Assisted, Macaca mulatta, Magnetic Resonance Imaging, Male, Memory, Short-Term, Neurons, Post-Synaptic Density, Prefrontal Cortex, Rats, Receptors, Metabotropic Glutamate, Spatial Learning, Subcellular Fractions
Show Abstract · Added April 6, 2017
The newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory. These circuits are weakened by increased cAMP-K+ channel signaling, and are a focus of pathology in schizophrenia, aging, and Alzheimer's disease. Cognitive deficits in these disorders are increasingly associated with insults to mGluR3 metabotropic glutamate receptors, while reductions in mGluR2 appear protective. This has been perplexing, as mGluR3 has been considered glial receptors, and mGluR2 and mGluR3 have been thought to have similar functions, reducing glutamate transmission. We have discovered that, in addition to their astrocytic expression, mGluR3 is concentrated postsynaptically in spine synapses of layer III dlPFC, positioned to strengthen connectivity by inhibiting postsynaptic cAMP-K+ channel actions. In contrast, mGluR2 is principally presynaptic as expected, with only a minor postsynaptic component. Functionally, increase in the endogenous mGluR3 agonist, N-acetylaspartylglutamate, markedly enhanced dlPFC Delay cell firing during a working memory task via inhibition of cAMP signaling, while the mGluR2 positive allosteric modulator, BINA, produced an inverted-U dose-response on dlPFC Delay cell firing and working memory performance. These data illuminate why insults to mGluR3 would erode cognitive abilities, and support mGluR3 as a novel therapeutic target for higher cognitive disorders.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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18 MeSH Terms