Regulation of Thalamic and Cortical Network Synchrony by Scn8a

Makinson, Christopher D.; Tanaka, Brian S.; Sorokin, Jordan M.; Wong, Jennifer C.; Christian, Catherine A.; Goldin, Alan L.; Escayg, Andrew; Huguenard, John R.

doi:10.1016/j.neuron.2017.01.031

Cited by 102 publications

(139 citation statements)

References 79 publications

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“…With an array, we recorded multi-unit (MU) activity within the nRT and VB thalamus (Figure 5A). Optical activation of PV neurons evoked rhythmic oscillatory bursting activity in VB (Figure 5B), similar to previous work using electrical stimulations of the internal capsule (Huntsman et al, 1999; Makinson et al, 2017; Paz et al, 2011a, 2013; Barthó et al, 2014). Activation of SOM cells in the nRT evoked firing in VPL but not in VPM (Figure 5B).…”

Section: Resultssupporting

confidence: 88%

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Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms

et al. 2017

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SUMMARY Integrative brain functions depend on widely distributed, rhythmically coordinated computations. Through its long-ranging connections with cortex and most senses, the thalamus orchestrates the flow of cognitive and sensory information. Essential in this process, the nucleus reticularis thalami (nRT) gates different information streams through its extensive inhibition onto other thalamic nuclei; however, we lack an understanding of how different inhibitory neuron subpopulations in nRT function as gatekeepers. We dissociated the connectivity, physiology, and circuit functions of neurons within rodent nRT, based on parvalbumin (PV) and somatostatin (SOM) expression, and validated the existence of such populations in human nRT. We found that PV but not SOM cells are rhythmogenic, and that PV and SOM neurons are connected to and modulate distinct thalamocortical circuits. Notably, PV but not SOM neurons modulate somatosensory behavior and disrupt seizures. These results provide a conceptual framework for how nRT may gate incoming information to modulate brain-wide rhythms.

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Section: Resultssupporting

confidence: 88%

“…We used horizontal thalamic slices that conserve the connectivity between the nRT and VB thalamus (VB = VPM + VPL), in which we could assess nRT-VB intra-thalamic network oscillations independent of other structures (e.g., cortex) (Huntsman et al, 1999; Paz et al, 2011a, 2013; Makinson et al, 2017). …”

Section: Resultsmentioning

confidence: 99%

Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms

et al. 2017

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“…Previously, it has been hypothesized that LOF variants would not cause epilepsy, but rather present with ID with or without motor function abnormalities, such as ataxia . However, Blanchard et al also describe a patient with epilepsy and ID, carrying an LOF variant, and two existing Scn8a knockout mice models support the notion of epilepsy also being a feature of LOF of NaV1.6 . Other ion channel genes including SCN2A have been shown to have a similar clinical picture, where both GOF and LOF variants may cause epilepsy.…”

Section: Discussionmentioning

confidence: 99%

The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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Summary Objective Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A‐related epilepsies. Methods A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results We found 36 probands who presented with an SCN8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance With this study, we explore the electroclinical features of an intermediate SCN8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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“…; Lorincz & Nusser, ; Makinson et al . ), although Nav1.1 is considered to be the primary driving force for action potential initiation, and thus for excitability of most inhibitory neurons. The functional significance of Nav1.6 in inhibitory interneurons is largely unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Although some evidence indicates a role for Nav1.6 in establishing synaptic inhibition in the thalamic network (Makinson et al . ), conditional expression of the R1872W mutation in mouse inhibitory neurons did not induce seizures, whereas expression in excitatory neurons did (Bunton‐Stasyshyn et al . ).…”

Section: Introductionmentioning

confidence: 99%

Distinct functional alterations in SCN8A epilepsy mutant channels

Pan

Cummins

2019

The Journal of Physiology

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Key points Mutations in the SCN8A gene cause early infantile epileptic encephalopathy. We characterize a new epilepsy‐related SCN8A mutation, R850Q, in the human SCN8A channel and present gain‐of‐function properties of the mutant channel. Systematic comparison of R850Q with three other SCN8A epilepsy mutations, T761I, R1617Q and R1872Q, identifies one common dysfunction in resurgent current, although these mutations alter distinct properties of the channel. Computational simulations in two different neuron models predict an increased excitability of neurons carrying these mutations, which explains the over‐excitation that underlies seizure activities in patients. These data provide further insight into the mechanism of SCN8A‐related epilepsy and reveal subtle but potentially important distinction of functional characterization performed in the human vs. rodent channels. Abstract SCN8A is a novel causal gene for early infantile epileptic encephalopathy. It is well accepted that gain‐of‐function mutations in SCN8A underlie the disorder, although the remarkable heterogeneity of its clinical presentation and poor treatment response demand a better understanding of the disease mechanisms. Here, we characterize a new epilepsy‐related SCN8A mutation, R850Q, in human Nav1.6. We show that it is a gain‐of‐function mutation, with a hyperpolarizing shift in voltage dependence of activation, a two‐fold increase of persistent current and a slowed decay of resurgent current. We systematically compare its biophysics with three other SCN8A epilepsy mutations, T767I, R1617Q and R1872Q, in the human Nav1.6 channel. Although all of these mutations are gain‐of‐function, the mutations affect different aspects of channel properties. One commonality that we discovered is an alteration of resurgent current kinetics, although the mechanisms by which resurgent currents are augmented remain unclear for all of the mutations. Computational simulations predict an increased excitability of neurons carrying these mutations with differential enhancement by open channel blockade.

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Regulation of Thalamic and Cortical Network Synchrony by Scn8a

Cited by 102 publications

References 79 publications

Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms

Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms

The spectrum of intermediate SCN8A‐related epilepsy

Distinct functional alterations in SCN8A epilepsy mutant channels

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