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000258241 037__ $$aDZNE-2023-00587
000258241 041__ $$aEnglish
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000258241 1001_ $$0P:(DE-HGF)0$$aMasala, Nicola$$b0
000258241 245__ $$aTargeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.
000258241 260__ $$aOxford$$bOxford Univ. Press$$c2023
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000258241 520__ $$aMemory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.
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000258241 650_7 $$2Other$$acalcium imaging
000258241 650_7 $$2Other$$acognitive comorbidities
000258241 650_7 $$2Other$$adendritic integration
000258241 650_7 $$2Other$$adendritic spike
000258241 650_7 $$2Other$$aepilepsy
000258241 650_7 $$2NLM Chemicals$$aICA-121431
000258241 650_7 $$2NLM Chemicals$$aAcetamides
000258241 650_2 $$2MeSH$$aMice
000258241 650_2 $$2MeSH$$aAnimals
000258241 650_2 $$2MeSH$$aDendrites: physiology
000258241 650_2 $$2MeSH$$aHippocampus: physiology
000258241 650_2 $$2MeSH$$aAcetamides: metabolism
000258241 650_2 $$2MeSH$$aPyramidal Cells: metabolism
000258241 650_2 $$2MeSH$$aEpilepsy: metabolism
000258241 650_2 $$2MeSH$$aAction Potentials: physiology
000258241 7001_ $$0P:(DE-HGF)0$$aPofahl, Martin$$b1
000258241 7001_ $$0P:(DE-HGF)0$$aHaubrich, André N$$b2
000258241 7001_ $$aSameen Islam, Khondker Ushna$$b3
000258241 7001_ $$aNikbakht, Negar$$b4
000258241 7001_ $$aPasdarnavab, Maryam$$b5
000258241 7001_ $$aBohmbach, Kirsten$$b6
000258241 7001_ $$aAraki, Kunihiko$$b7
000258241 7001_ $$aKamali, Fateme$$b8
000258241 7001_ $$0P:(DE-2719)2811625$$aHenneberger, Christian$$b9$$udzne
000258241 7001_ $$aGolcuk, Kurtulus$$b10
000258241 7001_ $$aEwell, Laura A$$b11
000258241 7001_ $$aBlaess, Sandra$$b12
000258241 7001_ $$aKelly, Tony$$b13
000258241 7001_ $$0P:(DE-2719)2000044$$aBeck, Heinz$$b14$$eLast author$$udzne
000258241 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awac455$$gVol. 146, no. 6, p. 2399 - 2417$$n6$$p2399 - 2417$$tBrain$$v146$$x0006-8950$$y2023
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