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Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

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TLDR
It is suggested that insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction, with the hope of preventing epilepsy before seizures emerge.
Abstract
Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge Recent work has yielded important conceptual advances in this field We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction

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GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits

TL;DR: Current understanding of neocortical interneuron diversity and the properties that distinguish cell types are reviewed and it is illustrated how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.
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Cation-chloride cotransporters in neuronal development, plasticity and disease

TL;DR: This work has shown that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K+–Cl− cOTransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity.
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Neuron–glia interactions in the pathophysiology of epilepsy

TL;DR: The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.
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Reactive astrogliosis causes the development of spontaneous seizures.

TL;DR: Data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
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Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome.

TL;DR: It is shown that two major types of inhibitory neurons are impaired in generation of electrical signals by a DS mutation, whereas excitatory neurons are unaffected, and two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin- expressing, both have impaired excitability, resulting in disinhibition of the cortical network.
References
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Journal ArticleDOI

Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy

TL;DR: The results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/− heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
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Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.

TL;DR: Two mutations of the gene encoding the neuronal voltage-gated sodium channel (SCN1A), Thr875Met and Arg1648His, that co-segregate with the disorder in two families with GEFS+ linked to chromosome 2q are described, identifying a new disease gene for human inherited epilepsy.
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Defined types of cortical interneurone structure space and spike timing in the hippocampus

TL;DR: Roles for specific interneurone types are suggested in structuring the activity of pyramidal cells via their respective target domains, and accurately timing and synchronizingPyramidal cell discharge, rather than providing generalized inhibition.
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Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal Network

TL;DR: Evidence is provided that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation, by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-d-aspartate (NMDA) receptor NR1 in dentates gyrus granule Cells.
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REST and Its Corepressors Mediate Plasticity of Neuronal Gene Chromatin throughout Neurogenesis

TL;DR: It is shown that REST regulates the transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron, indicating that REST defines a gene set subject to plasticity in mature neurons.
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