Disordered breathing in a mouse model of Dravet syndrome

Kuo, Fu-Shan; Cleary, Colin; LoTurco, Joseph J.; Chen, Xinnian; Mulkey, Daniel K.

doi:10.7554/elife.43387

Cited by 54 publications

(54 citation statements)

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“…In DS mice with a Scn1a truncation mutation, selective deletion in inhibitory neurons resulted in complete mortality, while deletion in both excitatory and inhibitory neurons reduced the mortality level by 50% . Similarly, DS mice that harbor the Scn1a A1783V missense mutation solely within inhibitory neurons do not survive beyond P23 (Kuo et al, 2019), while those with global expression of the mutation, as done here, exhibit a mortality rate of ~50% (Fig. 1A).…”

Section: Increased Excitability Of Ca1 Pyramidal Neurons Is Limited Tmentioning

confidence: 55%

“…In support of the "inhibitory neuron" hypothesis, electrophysiological studies demonstrated impaired firing of multiple types of inhibitory neurons during the worsening stage, with no apparent change in the excitability of excitatory neurons (De Stasi et al, 2016;Favero et al, 2018;Goff and Goldberg, 2019;Han et al, 2012;Ogiwara et al, 2007;Rubinstein et al, 2015bRubinstein et al, , 2015aTai et al, 2014;Tsai et al, 2015). Moreover, selective deletion of Scn1a in inhibitory neurons was sufficient to cause seizures and premature mortality Kalume et al, 2013;Kuo et al, 2019;Ogiwara et al, 2013;Rubinstein et al, 2015a). Conversely, inhibitory neurons of the reticular thalamic nucleus were hyperexcitable (Ritter-Makinson et al, 2019), and reduced function of cortical parvalbumin (PV)-positive interneurons was shown to be limited only to the worsening stage (Favero et al, 2018).…”

Section: Introductionmentioning

confidence: 90%

“…DS mice harboring the global Scn1a A1783V mutation were generated by crossing males bearing the conditional Scn1a A1783V floxed allele (B6(Cg)-Scn1a tm1.1Dsf /J; strain 026133; The Jackson Laboratory) (Kuo et al, 2019;Styr et al, 2019) with CMV-Cre females (B6.C-Tg(CMVcre)1Cgn/J; strain 006054; The Jackson Laboratory). This breeding scheme was used due to the location of Cre on the X chromosome (Schwenk et al, 1995).…”

Section: Micementioning

confidence: 99%

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Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Almog

Brusel

Anderson

et al. 2019

Preprint

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Dravet syndrome (Dravet) epilepsy begins with febrile seizures followed by worsening to refractory seizures, with some improvement and stabilization toward adolescence. The neuronal basis of Dravet is debatable, with evidence favoring reduced inhibition or enhanced excitation. Focusing on the firing properties of hippocampal CA1 pyramidal neurons and oriens-lacunosum moleculare (O-LM) interneurons, we provide a comprehensive analysis of the activity of both cell types through the febrile, worsening and stabilization stages. Our data indicate a temporary increase in the excitability of CA1 pyramidal neurons during the febrile stage, which is fully reversed by the onset of spontaneous seizures. In contrast, reduced function of O-LM interneurons persisted from the febrile through the stabilization stages, with the greatest impairment of excitability occurring during the worsening stage. Thus, both excitatory and inhibitory neurons contribute to Dravet, indicating complex and reciprocal pathophysiological neuronal changes during the different stages of the disease.

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Section: Increased Excitability Of Ca1 Pyramidal Neurons Is Limited Tmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 90%

Section: Micementioning

confidence: 99%

See 1 more Smart Citation

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Almog

Brusel

Anderson

et al. 2019

Preprint

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“…DS mice, harboring the Scn1a A1783V missense mutation (Kuo et al, 2019;Ricobaraza et al, 2019;Styr et al, 2019), were asymptomatic for their first weeks of life. Spontaneous seizures were not observed prior to P16 (during routine handling) and were rare prior to P19.…”

Section: Ds Mice Recapitulate the Three Stages Of Dravetmentioning

confidence: 99%

Early EEG and behavioral alterations in Dravet mice

Fadila

Quinn

Maia

et al. 2020

Preprint

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Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stagerelated alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated.Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype. Highlights • Reduction in background EEG power in Dravet• Low EEG power correlates with the risk of premature death• Motor deficits and hyperactivity are evident as early as the febrile stage • Cognitive deficits and detection of increased anxiety begin at the worsening stage 10 min, and were selected from throughout the entire recording. Spikes were detected using LabChart 8 software (ADInstruments, Sydney, Australia). The threshold was set to 7 standard divisions, and their maximal allowed duration was set to 250 ms. Early motor activityWT and DS mice were tested from P8 to P11. Mice were individually placed in the middle of a 13 cm wide circle and the latency to cross the drawn borders of the circle was measured. The test was repeated three times and averaged. If the mouse was unable to cross the border of the circle within 1 min, the test was terminated. ...

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“…25 Likewise, mice carrying a conditional SCN1A missense mutation exhibit hypoventilation, apnea, and blunted response to CO 2 which can be explained by changes in neuronal excitability in the retrotrapezoid nucleus. 26 Mice lacking the Kv1.1 channel encoded by the KCNA1 gene have early-onset seizures and subsequent SUDEP. An array of respiratory dysfunction that progresses with age has been found in KCNA1 -null mice, 36 and the abnormal breathing pattern always precedes cardiac abnormalities during the ictal phase.…”

Section: Respiratory Mechanismsmentioning

confidence: 99%

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

Buchanan

2019

Epilepsy Curr

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, accounting for up to 17% of deaths in patients with epilepsy. The pathophysiology of SUDEP has remained unclear, largely because it is unpredictable and commonly unwitnessed. This poses a great challenge to studies in patients. Recently, there has been an increase in animal studies to try to better understand the pathophysiology of SUDEP. In this current review, we focus on developments through seizure-induced death models and the preventative strategies they may reveal.

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Disordered breathing in a mouse model of Dravet syndrome

Cited by 54 publications

References 53 publications

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Early EEG and behavioral alterations in Dravet mice

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

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