Focal Scn1a knockdown induces cognitive impairment without seizures

Bender, Alex C.; Natola, Heather; Ndong, Christian; Holmes, Gregory L.; Scott, Rod C.; Lenck-Santini, Pierre-Pascal

doi:10.1016/j.nbd.2012.12.021

Cited by 76 publications

(65 citation statements)

References 58 publications

(101 reference statements)

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“…A study in which Na v 1.1 was down-regulated in the medial septum showed that this led to a disruption in the septohippocampal network with impairments in hippocampal-dependent functions, but in the absence of any seizures. This strongly supports the view that there are direct negative cognitive effects of the mutation and that seizures are not required for cognitive impairment (Bender et al 2013). …”

Section: Genetic Etiologysupporting

confidence: 84%

Mechanisms Responsible for Cognitive Impairment in Epilepsy

Lenck-Santini

Scott

2015

Cold Spring Harb Perspect Med

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Epilepsy is often associated with cognitive and behavioral impairments that can have profound impact on the quality of life of patients. Although the mechanisms of cognitive impairment are not completely understood, we make an attempt to describe, from a systems perspective, how information processing is affected in epilepsy disorders. The aim of this review is to (1) define the nature of cognitive deficits associated with epilepsy, (2) review fundamental systems-level mechanisms underlying information processing, and (3) describe how information processing is dysfunctional in epilepsy and investigate the relative contributions of etiology, seizures, and interictal discharges (IDs). We conclude that these mechanisms are likely to be important and deserve more detailed scrutiny in the future.T he epilepsies are a group of disorders defined by the propensity for an individual to have epileptic seizures (Fisher et al. 2014). In addition to seizures, these common and serious neurological disorders are associated with cognitive and behavioral impairments (Berg and Scheffer 2011). The cognitive and behavioral impairments are critical determinants of the reductions in quality of life observed in patients with epilepsy (Ronen et al. 2003;Loring et al. 2004). It is, therefore, of major importance that the mechanisms underlying cognitive impairments are characterized as this is likely to lead to novel interventions that will ultimately improve the quality of life of people with epilepsy. Epilepsy is associated with a variety of physiological and molecular alterations at the level of changes in the genome, gene expression, receptor characteristics, peptides, and brain injury. These changes are not only responsible for seizures but also for functional abnormalities underlying cognitive impairment. It is likely that several of these mechanisms are occurring in concert, and, therefore, it is important to study the net effects of these alterations at the level of neural networks as this may also lead to novel interventions that could improve outcomes. The aims of this article are to (1) define the nature of cognitive deficits associated with epilepsy, (2) review fundamental systems-level mechanisms underlying information processing, and (3) describe how information processing is dysfunctional in epilepsy and investigate the relative contributions of etiology, seizures, and interictal discharges (IDs).

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Section: Genetic Etiologysupporting

confidence: 84%

Mechanisms Responsible for Cognitive Impairment in Epilepsy

Lenck-Santini

Scott

2015

Cold Spring Harb Perspect Med

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“…In contrast, SCN1A deletion within excitatory neurons of the forebrain does not produce epilepsy . This is further supported by the observation that focal deletion of SCN1A in basal forebrain neurons does not result in epilepsy, but causes dysregulation of hippocampal oscillations and spatial memory deficit (Bender et al 2013). Even more interestingly, combined deletion in both inhibitory and forebrain excitatory neurons ameliorates the seizure-related sudden death expected from the interneuronal CKO .…”

Section: Animal Models Of Early-life Epilepsymentioning

confidence: 71%

Neonatal and Infantile Epilepsy: Acquired and Genetic Models

Galanopoulou

Moshé

2015

Cold Spring Harb Perspect Med

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The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous sclerosis, and related genetic disorders, or IS of acquired etiology. These models start to generate the first therapeutic drugs, which have been specifically developed in immature animals. However, there are challenges in translating preclinical discoveries into clinically relevant findings. The advances made so far hold promise that the new insights may potentially have curative or disease-modifying potential for many of these devastating conditions. T he neonatal and infantile periods show relatively high age-adjusted incidence of epilepsy compared with other ages of life (Hauser et al. 1993). The etiology of newly diagnosed epilepsies at these ages also is distinct, showing greater representation of epilepsies of unknown, genetic, or congenital etiologies (Hauser et al. 1993). The semiology and syndromic phenotypes of epilepsies that first appear in this early life period are also distinct and often more fulminant, appearing with evident neurodevelopmental problems or regression (e.g., epileptic encephalopathies) or characteristic seizure types (e.g., infantile spasms [IS], multifocal clonic seizures) ( Table 1). In addition, the treatments for epilepsies of these age groups can be specialized, as is the case with the use of hormonal therapies (e.g., adrenocorticotropic hormone [ACTH] in certain epileptic encephalopathies). Given the serious repercussions for the development of these neonates and infants and the importance of finding better therapies with disease-modifying potential, several efforts have been made to create animal models of these conditions to increase our understanding and ability to treat them. Here, we will review selected animal models, genetic or induced, that address epilepsies and epileptic encephalopathies characteristic of neonates and infants.

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“…Comorbidities of Refractory Epilepsy decreased excitability of GABAergic cerebellar Purkinje cells caused by SCN1A mutation not only contributes to seizure but also can be linked with learning and behavioral dysfunction [30]. Epilepsy and cognitive comorbidities attribute to interictal frequent epileptiform discharges, which impair synaptic plasticity, neurogenesis and memory retrieval by inhibition of action potential firing through spine loss in pyramidal cells in hippocampal CA3 [31].…”

Section: Reviewmentioning

confidence: 99%

Comorbidities of Refractory Epilepsy and the Update Mechanism

Wang¹,

He²,

Luan³

2017

Neuropsychiatry

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Epilepsy is still an issue that perplexes the epileptologists worldwide, with a reported impact on 50 million populations. With the reconceptualization of epilepsy as a disease of brain networks, it is great timing to rethink epilepsy and those associated comorbidities, including cognitive and behavioral comorbidities, psychiatric comorbidities, cardiovascular disease and migraine. In this review, we introduce the state of the art of these comorbidities of refractory epilepsy, including etiology, epidemiology, manifestation and mechanism. As essential comorbidities of epilepsy share the network consistent with epilepsy, a series of recent studies of comorbidities of epilepsy supply a new perspective on epileptic network. It is possible to accelerate the progression of epilepsy by translating those exciting advances in epileptic network into routine clinical practice.

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Focal Scn1a knockdown induces cognitive impairment without seizures

Cited by 76 publications

References 58 publications

Mechanisms Responsible for Cognitive Impairment in Epilepsy

Mechanisms Responsible for Cognitive Impairment in Epilepsy

Neonatal and Infantile Epilepsy: Acquired and Genetic Models

Comorbidities of Refractory Epilepsy and the Update Mechanism

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