Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice

Mistry, Akshitkumar M.; Thompson, Christopher H.; Miller, Alison N.; Vanoye, Carlos G.; George, Alfred L.; Kearney, Jennifer A.

doi:10.1016/j.nbd.2014.01.006

Cited by 155 publications

(225 citation statements)

References 31 publications

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“…One hypothesis is that the inhibitory neurons express a higher percentage of the mutant Na V 1.1 channels than excitatory neurons. The sodium current densities in inhibitory neurons in the first Scn1a ϩ/Ϫ mouse model and the F1.Scn1a ϩ/Ϫ mouse model are reduced by 53% and 43%, respectively, consistent with Na V 1.1 being the major sodium channel subtype in these inhibitory neurons (Mistry et al 2014;Yu et al 2006). This interpretation is supported by detection of high levels of Na V 1.1 expression in inhibitory neurons (Ogiwara et al 2007(Ogiwara et al , 2013.…”

Section: Mousesupporting

confidence: 56%

“…Assuming pyramidal neurons express the remaining 58% of the Na V 1.1 protein in P12.5 mouse brain and assuming pyramidal neurons comprise ϳ70 -90% of neurons in mammal brains (Jinno and Kosaka 2010; Markram et al 2004), we can deduce that the average Na V 1.1 expression level is lower in pyramidal compared with interneurons. However, an average lower level of Na V 1.1 expression in pyramidal neurons does not translate into a lower percentage of Na V 1.1 compared with all sodium channels, because the total sodium current density is also lower in pyramidal neurons, ϳ37-65% of that in inhibitory neurons (Martin et al 2010;Mistry et al 2014;Yu et al 2006). Therefore, it is not clear if the percentage of mutant Na V 1.1 is lower in pyramidal neurons than in inhibitory neurons.…”

Section: Mousementioning

confidence: 99%

“…Both the Scn1a knockout model and the R1407X knockin model show a mild seizure phenotype on a 129SvJ background and a more severe phenotype on a C57BL/6J background (Ogiwara et al 2007;Rubinstein et al 2015;Yu et al 2006). A recent study systematically examined the cellular alterations caused by a Scn1a deletion in these two genetic backgrounds (Mistry et al 2014). They reported that F1.Scn1a ϩ/Ϫ mice, on a 50% 129S6/ SvEvTac and 50% C57BL/6J background, exhibit spontaneous seizures and premature death.…”

Section: Mousementioning

confidence: 99%

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Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

Schutte

Barragan

et al. 2016

Journal of Neurophysiology

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Schutte SS, Schutte RJ, Barragan EV, O'Dowd DK. Model systems for studying cellular mechanisms of SCN1A-related epilepsy. J Neurophysiol 115: 1755-1766, 2016. First published February 3, 2016 doi:10.1152/jn.00824.2015Mutations in SCN1A, the gene encoding voltage-gated sodium channel Na V 1.1, cause a spectrum of epilepsy disorders that range from genetic epilepsy with febrile seizures plus to catastrophic disorders such as Dravet syndrome. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. Distinct effects of individual SCN1A mutations on neuronal function are likely to contribute to variation in disease severity and response to treatment in patients. Several model systems have been used to explore seizure genesis in SCN1A epilepsies. In this article we review what has been learned about cellular mechanisms and potential new therapies from these model systems, with a particular emphasis on the novel model system of knockin Drosophila and a look toward the future with expanded use of patient-specific induced pluripotent stem cell-derived neurons.

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Section: Mousesupporting

confidence: 56%

Section: Mousementioning

confidence: 99%

Section: Mousementioning

confidence: 99%

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Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

Schutte

Barragan

et al. 2016

Journal of Neurophysiology

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“…Their findings reflect previous results, showing hypoexcitability of PV+ and SOM+ DS neurons with no change in pyramidal neuron excitability (5,9). They also show that DS brain slices have faster propagation of ictal discharges.…”

Section: Expecting the Unexpected: Lack Of In Vivo Network Defects Insupporting

confidence: 91%

Expecting the Unexpected: Lack of in Vivo Network Defects in an Scn1a Model of Dravet Syndrome

Hull¹,

Isom²

2016

Epilepsy Curr

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CommentaryDravet syndrome (DS) is a severe pediatric epileptic encephalopathy with disease onset in the first year of life. Patients have normal presentation before seizure onset and then experience frequent seizures, ataxia, cognitive deficits, and a high risk of sudden unexpected death in epilepsy (1). The majority of DS cases are caused by de novo loss-of-function mutations in SCN1A, encoding the voltage-gated sodium channel Na v 1.1, resulting in haploinsufficiency (2-4).Early studies in Scn1a −/+ mice showed selective reductions in excitability and sodium current density in hippocampal interneurons, with pyramidal neurons unaffected, at postnatal day (P)13 to 14 (4). These data pointed to selective impairment of GABAergic interneurons in DS, leading to disinhibition and epilepsy. Subsequent work with cell type specific Scn1a deletions to study the roles of inhibitory interneuron subtypes supported this hypothesis (5-7). However, work in DS patientderived induced pluripotent stem cell neurons and in DS mice during the time of disease onset (P21-24) suggested a role for increased pyramidal neuron excitability in pathogenesis (8, 9). Disease onset and severity are correlated with increased Scn1a−/+ hippocampal pyramidal neuron excitability compared to wildtype (WT), while interneuron excitability is decreased before and after disease onset (9). Regardless of contributions from other neuron types, interneurons are involved in various network oscillations, suggesting their dysfunction should translate to dramatic network effects in vivo (10).In their article in Cerebral Cortex, De Stasi et al. set out to address the in vivo network impacts of SCN1A-linked DS in mice. In vivo local field potential (LFP) and multiunit activity (MUA) recordings were performed in the somatosensory cortex of P16 to 18 WT and Scn1a −/+ mice. Importantly, Scn1a−/+ mice in this age range have not yet begun to exhibit seizures and have been shown using whole cell patch clamp in acute brain slices to have hypoexcitability of parvalbumin positive (PV+) and somatostatin positive (SOM+) interneurons of the cortex and hippocampus (4, 5, 9). Here, under urethane anesthesia, De Stasi et al. demonstrated that the only differences in the LFP power spectrum between genotypes are modest reductions in the δ (2-4 Hz) and θ (4-8 Hz) frequency bands when recording from superficial cortical layers. In deep layer recordings, no differences were found between genotypes in the LFP power spectrum at any frequency. To test if the subtle differences were due to anesthesia, experiments were repeated in awake animals; however, no differences were found in the LFP power spectrum at any frequency. In addition, no differences in neuronal spiking were detected in the MUA signal Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a −/+ mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the m...

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“…Hippocampal neuron dissociations were performed as described (33). All mutagenesis, heterologous expression, voltage-clamp, and current-clamp recordings were performed as described (33)(34)(35)(36)(37).…”

Section: Methodsmentioning

confidence: 99%

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Thompson

Hawkins

Kearney

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In the Scn2a Q54 mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered Na V 1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features in Scn2a Q54 mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model. Scn2a Q54 mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence in Scn2a Q54 mice with higher activity in F1.Q54 animals. Heterologously expressed Na V 1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability in Scn2a Q54 mice and may represent a therapeutic target for the treatment of epilepsy.epilepsy | voltage-gated sodium channel | CaMKII V oltage-gated sodium channels are essential for the generation and propagation of action potentials in excitable cells (1). These proteins exist as heteromultimeric complexes formed by a large pore-forming α-subunit and one or more auxiliary β-subunits (2). Function of voltage-gated sodium channels is influenced by multiple intracellular factors including protein-protein interactions, channel phosphorylation, and intracellular calcium. The auxiliary β-subunits and a family of FGF homologous factors (FHF) have been shown to modulate trafficking and functional properties of voltage-gated sodium channels (3-5). Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6, 7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8-10). Thus, differences in posttranslational modification of sodium channels may profoundly influence the physiology of excitable cells.Mutations in genes encoding neuronal voltage-gated sodium ch...

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Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice

Cited by 155 publications

References 31 publications

Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

Expecting the Unexpected: Lack of in Vivo Network Defects in an Scn1a Model of Dravet Syndrome

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

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