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Focal Scn1a knockdown induces cognitive impairment without seizures.

ABSTRACT: Cognitive impairment is a common comorbidity in pediatric epilepsy that can severely affect quality of life. In many cases, antiepileptic treatments fail to improve cognition. Therefore, a fundamental question is whether underlying brain abnormalities may contribute to cognitive impairment through mechanisms independent of seizures. Here, we examined the possible effects on cognition of Nav1.1 down-regulation, a sodium channel principally involved in Dravet syndrome but also implicated in other cognitive disorders, including autism and Alzheimer's disease. Using an siRNA approach to knockdown Nav1.1 selectively in the basal forebrain region, we were able to target a learning and memory network while avoiding the generation of spontaneous seizures. We show that reduction of Nav1.1 expression in the medial septum and diagonal band of Broca leads to a dysregulation of hippocampal oscillations in association with a spatial memory deficit. We propose that the underlying etiology responsible for Dravet syndrome may directly contribute to cognitive impairment in a manner that is independent from seizures.

SUBMITTER: Bender AC

PROVIDER: S-EPMC3628954 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Focal Scn1a knockdown induces cognitive impairment without seizures.

Bender Alex C AC Natola Heather H Ndong Christian C Holmes Gregory L GL Scott Rod C RC Lenck-Santini Pierre-Pascal PP

Neurobiology of disease 20130111

Cognitive impairment is a common comorbidity in pediatric epilepsy that can severely affect quality of life. In many cases, antiepileptic treatments fail to improve cognition. Therefore, a fundamental question is whether underlying brain abnormalities may contribute to cognitive impairment through mechanisms independent of seizures. Here, we examined the possible effects on cognition of Nav1.1 down-regulation, a sodium channel principally involved in Dravet syndrome but also implicated in other ...[more]

PMID: 23318929

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Project description:ObjectiveTo investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality.MethodsFBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality.ResultsIndividuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS.ConclusionsIn TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Project description:BackgroundMild cognitive impairment and cognitive impairment, no dementia, are emerging terms that encompass the clinical state between normal cognition and dementia in elderly people. Controversy surrounds their characterization, definition and application in clinical practice. In this article, we provide physicians with practical guidance on the definition, diagnosis and treatment of mild cognitive impairment and cognitive impairment, no dementia, based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.MethodsWe developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that had mild cognitive impairment or cognitive impairment, no dementia, as the outcome. Subsequent to the conference, we searched for additional articles published between January 2006 and January 2008. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.ResultsWe identified 2483 articles, of which 314 were considered to be relevant and of good or fair quality. From a synthesis of the evidence in these studies, we made 16 recommendations. In brief, family physicians should be aware that most types of dementia are preceded by a recognizable phase of mild cognitive decline. They should be familiar with the concepts of mild cognitive impairment and of cognitive impairment, no dementia. Patients with these conditions should be closely monitored because of their increased risk for dementia. Leisure activities, cognitive stimulation and physical activity could be promoted as part of a healthy lifestyle in elderly people and those with mild cognitive impairment. Vascular risk factors should be treated optimally. No other specific therapies can yet be recommended.InterpretationPhysicians will increasingly see elderly patients with mild memory loss, and learning an approach to diagnosing states such as mild cognitive impairment is now warranted. Close monitoring for progression to dementia, promotion of a healthy lifestyle and treatment of vascular risk factors are recommended for the management of patients with mild cognitive impairment.

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Focal Scn1a knockdown induces cognitive impairment without seizures.

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Focal Scn1a knockdown induces cognitive impairment without seizures.

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