Hippocampal deletion of Na
            <sub>V</sub>
            1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome

Stein, Rachael E; Kaplan, Joshua S.; Jin, Li; Catterall, William A.

doi:10.1073/pnas.1906833116

Cited by 56 publications

(59 citation statements)

References 42 publications

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“…An increase in core temperature causes generalized seizures in Scn1a ‐/+ mice 12 and in mice with local hippocampal Na V 1.1 ablation, 9 reflecting the early febrile seizures often observed in infants with Dravet syndrome 1,2 . We therefore tested whether seizures could also be induced by hyperthermia in our Scn1a ‐/+ (n = 7) and AAV‐GFP‐Cre‐injected Scn1a fl/fl (hippocampus: n = 4; cortex: n = 5) mice.…”

Section: Resultsmentioning

confidence: 99%

“…The hippocampus has been suggested as a primary driver of epileptiform activity in a mouse model of Dravet syndrome 8 . In addition, Stein et al 9 recently demonstrated that local ablation of Na V 1.1 channels restricted to hippocampus results in an increased sensitivity to thermally evoked seizures. Because patients with SCN1A mutations may manifest with focal (cortical) epilepsy, 10,11 the relevance of various brain regions is of interest.…”

Section: Introductionmentioning

confidence: 99%

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Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice

et al. 2020

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Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss‐of‐function of voltage‐gated NaV1.1 sodium channels, which are chiefly expressed in γ‐aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of NaV1.1 channels decreased the threshold for hyperthermia‐induced seizures. However, the effect of ablation of NaV1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the α1 subunit of NaV1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1‐/+ mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a‐/+ mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia‐induced seizures. In conclusion, local ablation of NaV1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice

et al. 2020

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“…There are conflicting results regarding the neuronal basis of Dravet, with evidence for reduced inhibition De Stasi et al, 2016;Ogiwara et al, 2007;Rubinstein et al, 2015b;Tai et al, 2014;Yu et al, 2006) that might be transient (Favero et al, 2018), as well as indications of increased activity of excitatory neurons (Liu et al, 2013;Mistry et al, 2014). Here, we focused on the hippocampal CA1 region, which has been shown to be important for Dravet epilepsy (Stein et al, 2019), examining the function of CA1 pyramidal neurons and stratum oriens interneurons (O-LM) at the three stages of Dravet. Within the CA1 microcircuit, recurrent collaterals of CA1 pyramidal cells activate O-LM interneurons, which in turn mediate feedback inhibition of these same excitatroy neurons (Klausberger and Somogyi, 2008;Müller and Remy, 2014;Scanziani and Pouille, 2004) (Fig.…”

Section: Reduced Intrinsic Excitability Of O-lm Cells At the Onset Ofmentioning

confidence: 95%

“…Here, we focused on the hippocampal CA1 region, which has been shown to be important for Dravet epilepsy (Stein et al, 2019), examining the function of CA1 pyramidal neurons and stratum oriens interneurons (O-LM) at the three stages of Dravet. Within the CA1 microcircuit, recurrent collaterals of CA1 pyramidal cells activate O-LM interneurons, which in turn mediate feedback inhibition of these same excitatroy neurons (Klausberger and Somogyi, 2008;Müller and Remy, 2014;Scanziani and Pouille, 2004) (Fig.…”

Section: Reduced Intrinsic Excitability Of O-lm Cells At the Onset Ofmentioning

confidence: 99%

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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“…Nevertheless, studies of adult DS mice, featuring selective deletion of Scn1a in parvalbumin-and somatostatinexpressing inhibitory neurons, reported mild epilepsy with cognitive deficit (Rubinstein et al, 2015a;Tatsukawa et al, 2018). Similarly, local deletions of Scn1a in the hippocampus caused either mild or no epilepsy, with cognitive deficits (Bender et al, 2016(Bender et al, , 2013Stein et al, 2019). These results suggest that cognitive deficits, similarly to motor impairment and hyperactivity may also be independent of the epilepsy.…”

Section: Behavioral Alterations In Ds Mice During the Febrile Stagementioning

confidence: 94%

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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Hippocampal deletion of Na _V 1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome

Cited by 56 publications

References 42 publications

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice

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

Early EEG and behavioral alterations in Dravet mice

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Hippocampal deletion of Na V 1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome

Cited by 56 publications

References 42 publications

Focal and generalized seizure activity after local hippocampal or cortical ablation of NaV1.1 channels in mice

Focal and generalized seizure activity after local hippocampal or cortical ablation of NaV1.1 channels in mice

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

Early EEG and behavioral alterations in Dravet mice

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Hippocampal deletion of Na _V 1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 channels in mice