Epilepsy articles within Nature Communications

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  • Article
    | Open Access

    Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.

    • Atsushi Takata
    • , Mitsuko Nakashima
    •  & Naomichi Matsumoto

  • Article
    | Open Access

    Spike and wave discharge (SWD) activity is seen during absence seizures and is thought to be thalamocortical in origin. Here, the authors show that SWDs are initiated through the impaired corticostriatal excitatory transmissions onto striatal fast spiking interneurons.

    • Hiroyuki Miyamoto
    • , Tetsuya Tatsukawa
    •  & Kazuhiro Yamakawa

  • Article
    | Open Access

    Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.

    • Jennifer Friedman
    • , Desiree E. Smith
    •  & Joseph G. Gleeson

  • Article
    | Open Access

    tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

    • Aleksandra Siekierska
    • , Hannah Stamberger
    •  & Peter De Jonghe

  • Article
    | Open Access

    Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.

    • Bassel Abou-Khalil
    • , Pauls Auce
    •  & Fritz Zimprich

  • Article
    | Open Access

    The identification of new drug targets is highly challenging, particularly for diseases of the brain. This study describes a general computational gene regulatory framework called CRAFT for drug target discovery, and the authors use CRAFT to identify the microglial membrane receptor Csf1R as a potential therapeutic target for epilepsy.

    • Prashant K. Srivastava
    • , Jonathan van Eyll
    •  & Michael R. Johnson

  • Article
    | Open Access

    High frequency oscillations (HFO) are a promising biomarker for identifying epileptogenic zones without the need to monitor spontaneous seizure episodes. Here the authors report that there is much variability in the location of HFOs offering a note of caution toward using HFO locations from short recordings as a guide for surgery.

    • Stephen V. Gliske
    • , Zachary T. Irwin
    •  & William C. Stacey

  • Article
    | Open Access

    Absence epilepsy is associated with frequent generalized spike-wave seizures and loss of awareness. Here the authors use 2-photon calcium imaging of primary visual cortex in a genetic mouse model of absence epilepsy and find that cortical neurons are less active and more loosely coupled to the seizure EEG signature than previously believed.

    • Jochen Meyer
    • , Atul Maheshwari
    •  & Stelios Smirnakis

  • Article
    | Open Access

    LGI1 is an epilepsy-related gene that encodes a secreted neuronal protein. Here the authors present the crystal structure of LGI1 bound to its receptor ADAM22, which provides structural insights into epilepsy-causing LGI1 mutations and might facilitate the development of novel anti-epilepsy drugs.

    • Atsushi Yamagata
    • , Yuri Miyazaki
    •  & Shuya Fukai

  • Article
    | Open Access

    N-methyl-d-aspartate-receptors (NMDARs) are glutamate receptors critical for synaptic transmission, plasticity, and cognition. Here, the authors look at four neurodevelopmental disease-related mutations of NMDAR, gaining insight into binding of Mg2+ and mechanism of memantine, an NMDAR antagonist.

    • Laura Fedele
    • , Joseph Newcombe
    •  & Trevor G. Smart

  • Article
    | Open Access

    The ability to identify periods of heightened seizure risk could enable new treatments for patients with epilepsy. Here, the authors describe long term EEG recordings from 37 patients which allow them to identify multi-day fluctuations in interictal activity.

    • Maxime O. Baud
    • , Jonathan K. Kleen
    •  & Vikram R. Rao

  • Article
    | Open Access

    Focal cortical seizures result from local and widespread propagation of excitatory activity. Here the authors employ widefield calcium imaging in mouse visual areas to demonstrate that these seizures start as local synchronous activation and then propagate along the connectivity that underlies normal sensory processing.

    • L. Federico Rossi
    • , Robert C. Wykes
    •  & Matteo Carandini

  • Article
    | Open Access

    The authors record both local and long-range neural activity during human epileptic seizures to study the underlying multi-scale dynamics. They find that coupling of activity across spatial scales increases during seizures through propagating waves that are fit by a model that combines neural activity and potassium concentration dynamics.

    • L-E Martinet
    • , G. Fiddyment
    •  & M. A. Kramer

  • Article
    | Open Access

    Chloride regulation is important for setting GABAergic reversal potential, though tools to manipulate chloride levels are limited. Here, the authors combine Archaerhodopsin with a chloride channel opsin to generate an optogenetic chloride extrusion strategy, ‘Cl-out’, which they demonstrate in hippocampal slices.

    • Hannah Alfonsa
    • , Jeremy H. Lakey
    •  & Andrew J. Trevelyan

  • Article
    | Open Access

    Epileptic brains display inhibitory restraint as manifested by the spread of synchronized activities being delayed in timing. Here, Elliot Smith and colleagues show fast-moving traveling wave that originates from the edge of ictal wavefront with subsequent depolarization and multiunit firing in the seizing brain regions in epileptic patients.

    • Elliot H. Smith
    • , Jyun-you Liou
    •  & Catherine A. Schevon

  • Article |

    Munc18-1 binds trans-SNARE complexes and promotes membrane fusion in vitro. Here the authors provide genetic evidence that this trans-SNARE-regulating function plays an essential role in synaptic releases in neurons, and show that this function is disrupted by a disease-causing Munc18-1 mutation.

    • Chong Shen
    • , Shailendra S. Rathore
    •  & Jingshi Shen

  • Article
    | Open Access

    Temporal lobe epilepsy can cause ionic imbalance in the brain and alter transcriptional activities. Here, van Loo et al.show that the increase in neuronal zinc following status epilepticus can induce transcriptional change via metal-regulatory transcription factor 1, and alter voltage-gated calcium channel CaV3.2 and intrinsic neuronal excitability.

    • Karen M. J. van Loo
    • , Christina Schaub
    •  & Albert J. Becker

  • Article
    | Open Access

    The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding geneSLC12A5, which impair normal synaptic function associated with early-onset epilepsy.

    • Tommy Stödberg
    • , Amy McTague
    •  & Manju A. Kurian

  • Article
    | Open Access

    Aberrant hippocampal neurogenesis often occurs after acute seizures that produce epilepsy and cognitive impairment but the role of neurogenesis in the development of epilepsy is unclear. Here the authors suppress adult neurogenesis in mice preceding seizures and show that it reduces subsequent chronic seizure frequency and epilepsy-associated cognitive decline.

    • Kyung-Ok Cho
    • , Zane R. Lybrand
    •  & Jenny Hsieh

  • Article
    | Open Access

    Membrane depolarization during increased neuronal activity as seen during epilepsy has been suggested to easily reverse neuronal GABA transporters. Here the authors use modelling and experimental data and challenge this view by showing that synaptic GABA release during excessive neuronal firing averts reversal of GABA uptake.

    • Leonid Savtchenko
    • , Maria Megalogeni
    •  & Ivan Pavlov

  • Article |

    Neurological disorders such as temporal lobe epilepsy (TLE) are known to be regulated by gene networks. In this study, the authors describe a genome-wide approach that uses samples of hippocampal tissue from patients with TLE, to identify the gene Sestrin 3 (SESN3) as a positive regulator of the disease.

    • Michael R. Johnson
    • , Jacques Behmoaras
    •  & Enrico Petretto

  • Article
    | Open Access

    Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.

    • N. Lozovaya
    • , S. Gataullina
    •  & N. Burnashev

  • Article |

    The transmembrane protein Elfn1 is implicated in synaptic plasticity. Tomioka et al. identify Elfn1 mutations in epilepsy and attention deficit hyperactivity disorder (ADHD) patients, and show that loss of Elfn1in mice results in seizures, ADHD-like behaviour and impaired development of excitatory synapses.

    • Naoko H. Tomioka
    • , Hiroki Yasuda
    •  & Jun Aruga

  • Article
    | Open Access

    Focal epilepsy is difficult to treat with currently available drugs or surgical approaches. Kätzel et al.express mutant inhibitory receptors in the brains of rats with focal epilepsy and selectively activate these receptors by an exogenous compound, which results in region- and time-specific suppression of focal seizures

    • Dennis Kätzel
    • , Elizabeth Nicholson
    •  & Dimitri M. Kullmann

  • Article |

    Ion channel mutations are implicated in epilepsy but post-translational modification of these channels is poorly understood. Here, Liu et al.show that mice with mutations in a specific E3 ubiquitin ligase that post-translationally modifies voltage-activated potassium channels may also contribute to epilepsy symptoms.

    • Jiye Liu
    • , Jia Ye
    •  & Yong Cang

  • Article |

    N-methyl-D-aspartate receptors (NMDARs) are key regulators of neuronal excitability in the brain and NMDAR mutations are implicated in epilepsy. Here, the authors identify a NMDAR subunit mutation in a child with epileptic encephalopathy, and show that this mutation increases the activity of NMDAR channels.

    • Hongjie Yuan
    • , Kasper B. Hansen
    •  & Stephen F. Traynelis

  • Article
    | Open Access

    Temporal lobe epilepsy in adults does not always respond to treatment. Krook-Magnuson and colleagues use optogenetics to inhibit and activate excitatory and inhibitory neurons, respectively, in a mouse model of temporal lobe epilepsy, and find that they can stop seizures on a moment-to-moment basis.

    • Esther Krook-Magnuson
    • , Caren Armstrong
    •  & Ivan Soltesz

  • Article
    | Open Access

    Seizure activity in the brain is characterized by the recruitment of cortical neuronal activity. Schevon and colleagues study seizure activity in human subjects and find that the recruitment of neurons is hypersynchronous and that there is an intrinsic restraint on the propagation of this activity.

    • Catherine A. Schevon
    • , Shennan A. Weiss
    •  & Andrew J. Trevelyan

  • Article |

    Speech is encoded by the firing patterns of speech-controlling neurons in different regions of the brain, which Tankus and colleagues analyse in this study. They find highly specific encoding of vowels in medial–frontal neurons and nonspecific tuning in superior temporal gyrus neurons.

    • Ariel Tankus
    • , Itzhak Fried
    •  & Shy Shoham

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