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Two characteristic currents of cerebellar Purkinje cells are reduced in mice with mutation in Scn8a. Left, resurgent current and persistent currents; right, complex spiking. Reprinted from Raman et al. (1997) with permission of the publisher.
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Allelic mutations of Scn8a in the mouse have revealed the range of neurological disorders that can result from alternations of one neuronal sodium channel. Null mutations produce the most severe phenotype, with motor neuron failure leading to paralysis and juvenile lethality. Two less severe mutations cause ataxia, tremor, muscle weakness, and dyst...
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... most striking cellular effect of the Scn8a mutations described to date is the effect on cere- bellar Purkinje cells. These cells are distinguished by their spontaneous slow firing pattern and their ability to generate a series of action potentials after stimulation. This complex spiking activity is thought to be involved in integration of signals for motor control. Recordings of currents from Pur- kinje cells demonstrate loss of complex spiking in both Scn8a tg and Scn8a jo mice (Figure 3, right panel). The similar effect of the null and the mis- sense mutation indicates that the Purkinje cell is particularly dependent on Scn8a. This functional requirement is consistent with the high level of Scn8a expression that was detected in Purkinje cells ( Schaller et al., 1995;Krzemien et al., 2000). Scn8a mutations also affect two other characteristic sodium currents of Purkinje cells, the persistent current and the resurgent current (Figure 3, left panel) ( Raman et al., 1997). It is interesting that the small change in voltage dependence of Scn8a jo has a profound effect on currents in Purkinje cells but does not impair the generation of action potentials in motor neurons. Cartwheel cells of the dorsal cochlear nucleus are ontologically related to cerebellar Purkinje cells and exibit similar firing patterns. Currents recorded from the dorsal cochlear nucleus in brain slices from Scn8a medJ and Scn8a jo mice demon- strated extensive loss of these cells as well (Chen et al., 1999). Persistent current is a feature of many pacemaker neurons and pyramidal cortical cells, and the med mutants alter these as well ( Raman et al., 1997;Maurice et al., ...
Context 2
... most striking cellular effect of the Scn8a mutations described to date is the effect on cere- bellar Purkinje cells. These cells are distinguished by their spontaneous slow firing pattern and their ability to generate a series of action potentials after stimulation. This complex spiking activity is thought to be involved in integration of signals for motor control. Recordings of currents from Pur- kinje cells demonstrate loss of complex spiking in both Scn8a tg and Scn8a jo mice (Figure 3, right panel). The similar effect of the null and the mis- sense mutation indicates that the Purkinje cell is particularly dependent on Scn8a. This functional requirement is consistent with the high level of Scn8a expression that was detected in Purkinje cells ( Schaller et al., 1995;Krzemien et al., 2000). Scn8a mutations also affect two other characteristic sodium currents of Purkinje cells, the persistent current and the resurgent current (Figure 3, left panel) ( Raman et al., 1997). It is interesting that the small change in voltage dependence of Scn8a jo has a profound effect on currents in Purkinje cells but does not impair the generation of action potentials in motor neurons. Cartwheel cells of the dorsal cochlear nucleus are ontologically related to cerebellar Purkinje cells and exibit similar firing patterns. Currents recorded from the dorsal cochlear nucleus in brain slices from Scn8a medJ and Scn8a jo mice demon- strated extensive loss of these cells as well (Chen et al., 1999). Persistent current is a feature of many pacemaker neurons and pyramidal cortical cells, and the med mutants alter these as well ( Raman et al., 1997;Maurice et al., ...
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... 29,31,70,71 Its global deletion develops ataxia and tremors of hindlimbs progressing to paralysis. 72 The disrupted function of the motor system likely involves central motor control impairments but not that of the CPG for locomotion since it operates normally in Nav1.6 À/À mice (Figures S7A and S7B). The selective inactivation of Nav1.6 in cerebellar Purkinje neurons results in ataxia and tremor symptoms without paresis of hindlimbs. ...
Persistent sodium current (INaP) in the spinal locomotor network promotes two distinct nonlinear firing patterns: a self-sustained spiking triggered by a brief excitation in bistable motoneurons and bursting oscillations in interneurons of the central pattern generator (CPG). Here, we identify the NaV channels responsible for INaP and their role in motor behaviors. We report the axonal Nav1.6 as the main molecular player for INaP in lumbar motoneurons. The inhibition of Nav1.6, but not of Nav1.1, in motoneurons impairs INaP, bistability, postural tone, and locomotor performance. In interneurons of the rhythmogenic CPG region, both Nav1.6 and Nav1.1 equally mediate INaP. Inhibition of both channels is required to abolish oscillatory bursting activities and the locomotor rhythm. Overall, Nav1.6 plays a significant role both in posture and locomotion by governing INaP-dependent bistability in motoneurons and working in tandem with Nav1.1 to provide INaP-dependent rhythmogenic properties of the CPG.
... Mouse models of SCN8A/Na V 1.6 DEE pathogenic variants are available: a standard global knock-in of the N1768D variant (Wagnon et al., 2015) and a conditional floxed knock-in of the R1872W variant to the clinical features of SCN8A/Na V 1.6 DEE. In contrast, spontaneous mouse models carrying LOF Na V 1.6 pathogenic variants (Meisler et al., 2004) show a phenotype that is similar to that of patients with intellectual disability and/or movement disorders without prominent epilepsy. Non-convulsive absence seizures have been observed in heterozygous SCN8A/Na V 1.6 knock-out mice, and floxed models with selective knock-out in selective neurons have shown that they are generated by reduced desynchronizing recurrent synaptic inhibition in neurons of the thalamic reticular nucleus leading to prolonged synchronized inhibitory output affecting the timing of thalamocortical oscillations and to spikes and wave discharges (absence-like phenotype) (Makinson et al., 2017). ...
The past two decades have witnessed a wide range of studies investigating genetic variants of voltage-gated sodium (NaV ) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in NaV α and β subunits, as well as of some relevant interacting proteins (FGF12/FHF1, PRRT2, and Ankyrin-G). Notably, variants of all these genes can induce either gain- or loss-of-function of NaV leading to either neuronal hyperexcitability or hypoexcitability. We present the results of functional studies obtained with different experimental models, highlighting that they should be interpreted considering the features of the experimental system used. These systems are models, but they have allowed us to better understand pathophysiological issues, ameliorate diagnostics, orientate genetic counseling, and select/develop therapies within a precision medicine framework. These studies have also allowed us to gain insights into the physiological roles of different NaV channels and of the cells that express them. Overall, our review shows the progress that has been made, but also the need for further studies on aspects that have not yet been clarified. Finally, we conclude by highlighting some significant themes of general interest that can be gleaned from the results of the work of the last two decades.
... Mutations of the Scn8a gene have distinct behavioral consequences in mice, which have been used to model a range of neurological disorders (Meisler, Plummer, Burgess, Buchner, & Sprunger, 2004). Scn8a encodes a sodium voltage-gated channel alpha subunit. ...
... Scn8a encodes a sodium voltage-gated channel alpha subunit. While complete null mutations result in paralysis and early lethality, less severe mutations can cause dystonia, tremor, muscle weakness, and other motor abnormalities (Hamann, Meisler, & Richter, 2003;Meisler et al., 2004;Sprunger, Escayg, Tallaksen-Greene, Albin, & Meisler, 1999). Notably, the Scn8a mutation is lethal on the C57BL/6J background but not on the C3H background, which may be mediated by the protective modifier gene Scnm1 (Sprunger, Escayg, Tallaksen-Greene, Albin, & Meisler, 1999). ...
... Mutations in Scn8a generally reduce neuronal excitability, especially in cerebellar neurons. In mice with null and hypomorphic Scn8a alleles, Purkinje cells exhibited abnormal subthreshold sodium currents as well as spontaneous and evoked firing patterns (Jones et al., 2016;Meisler et al., 2004;Raman et al., 1997). Namely, the persistent sodium current and resurgent sodium current were reported to be greatly reduced and complex spikes could not be elicited. ...
Dystonia is currently ranked as the third most prevalent motor disorder. It is typically characterized by involuntary muscle over- or co-contractions that can cause painful abnormal postures and jerky movements. Dystonia is a heterogenous disorder-across patients, dystonic symptoms vary in their severity, body distribution, temporal pattern, onset, and progression. There are also a growing number of genes that are associated with hereditary dystonia. In addition, multiple brain regions are associated with dystonic symptoms in both genetic and sporadic forms of the disease. The heterogeneity of dystonia has made it difficult to fully understand its underlying pathophysiology. However, the use of animal models has been used to uncover the complex circuit mechanisms that lead to dystonic behaviors. Here, we summarize findings from animal models harboring mutations in dystonia-associated genes and phenotypic animal models with overt dystonic motor signs resulting from spontaneous mutations, neural circuit perturbations, or pharmacological manipulations. Taken together, an emerging picture depicts dystonia as a result of brain-wide network dysfunction driven by basal ganglia and cerebellar dysfunction. In the basal ganglia, changes in dopaminergic, serotonergic, noradrenergic, and cholinergic signaling are found across different animal models. In the cerebellum, abnormal burst firing activity is observed in multiple dystonia models. We are now beginning to unveil the extent to which these structures mechanistically interact with each other. Such mechanisms inspire the use of pre-clinical animal models that will be used to design new therapies including drug treatments and brain stimulation.
... Overall, knockin mice indicate that SCN8A GoF mutations are sufficient to induce hyperexcitability of some subtypes of excitatory neurons, generating severe seizures and a lethal phenotype. In contrast, spontaneous mouse models carrying LoF SCN8A mutations (309) show a phenotype similar to that of patients with intellectual disability and/or movement disorders without epilepsy. ...
Developmental and epileptic encephalopathies are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures, EEG abnormalities, on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both non-genetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs, of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.
... Additionally, elevated persistent currents have been shown to increase the likelihood of premature firing in neurons [87] and can undergo extensive regulation by various protein-protein interactions and PTMs [11,88,89]. The physiological importance of persistent currents is highlighted by mutational studies that either decrease or increase Na v 1.6 persistent current generation [79,80,87,[90][91][92]. For example, while cerebellar Purkinje neurons isolated from Scn8a null mice display a 35% decrease in the transient sodium current, they display an even larger 70% reduction in the persistent current in addition to reduced repetitive firing capabilities compared to WT littermates [80]. ...
... Conversely, transgenic mice harboring mutations that increase persistent Na v 1.6 sodium current exhibit neuronal hyperexcitability, spontaneous seizure activity, and even sudden unexplained death [87,91,92]. Thus, persistent currents generated by Na v 1.6 can significantly impact the initiation and propagation of APs in synaptic transmission [87,90,[93][94][95]. persistent currents is highlighted by mutational studies that either decrease or increase Nav1.6 persistent current generation [79,80,87,[90][91][92]. ...
... Conversely, transgenic mice harboring mutations that increase persistent Na v 1.6 sodium current exhibit neuronal hyperexcitability, spontaneous seizure activity, and even sudden unexplained death [87,91,92]. Thus, persistent currents generated by Na v 1.6 can significantly impact the initiation and propagation of APs in synaptic transmission [87,90,[93][94][95]. persistent currents is highlighted by mutational studies that either decrease or increase Nav1.6 persistent current generation [79,80,87,[90][91][92]. For example, while cerebellar Purkinje neurons isolated from Scn8a null mice display a 35% decrease in the transient sodium current, they display an even larger 70% reduction in the persistent current in addition to reduced repetitive firing capabilities compared to WT littermates [80]. ...
Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.
... The predominant sodium channel isoforms expressed in cerebellar Purkinje cells are Nav1.1 and Nav1.6 channels (Kalume et al., 2007;Ransdell & Nerbonne, 2018;Schaller & Caldwell, 2003). These channels are important in shaping the waveforms of APs and control the rate of repetitive firing in Purkinje cells (Kalume et al., 2007;Levin et al., 2006;Meisler et al., 2004;. The deletion or mutation in genes and disruption in ion channel clustering will impair normal Purkinje cell function. ...
Duchenne muscular dystrophy (DMD) is a rapidly progressive X-linked recessive disease affecting about 1 in 3500 live male births. It is caused by mutations in the dystrophin gene, which result in the loss of dystrophin or expression of a non-functional truncated protein product. Full-length dystrophin is mainly expressed in muscles and the central nervous system. In addition to the degeneration of skeletal musculature, about one-third of patients with DMD display various degrees of intellectual impairment, commonly found with intelligence quotient (IQ) scores of one standard deviation below (IQ of 85) the normal population mean (IQ of 100). However, the mechanism underlying the cognitive deficits in DMD remains unclear and no effective treatment is available to reverse this condition in the affected individual. Recent studies showed that the life span of DMD patients today has increased from teens to their fourth decades. With longer survival, the quality of life becomes increasing important. Therefore, research on the cognitive aspect of DMD is as important as research on the muscular aspects because improvements in cognitive function will enhance the quality of life for the growing population of adult DMD patients. The aim of this thesis was to investigate the role of dystrophin in the central nervous system of the mdx mouse, a widely accepted murine model for DMD. This study employed the use of animal with different age groups, corresponding to young (3-4 months), adult (11-12 months), and aged (23-26 months). Adult and aged mdx mice are the focus in this study with findings from the older mouse especially valuable as, disease progression in aged mice closely resembling that of DMD. As numerous evidence has shown a high similarity between the specific cognitive dysfunctions seen in DMD (i.e. impaired verbal intelligence) and in patients with cerebellar lesions (i.e. language disorders), this study examined the function of cerebellar Purkinje cells in mdx mice using electrophysiological recording and calcium imaging. Overall, the data presented in this thesis provides new insights into the role of dystrophin in cerebellar Purkinje neurons. The findings suggest that dystrophin is important for normal inhibitory synaptic function, intrinsic electrophysiological properties, and calcium handling of the mature cerebellar Purkinje cells. The consequences of the absence of dystrophin including the altered GABAA receptor clustering and reduced peak amplitude of mIPSCs could be ameliorated when dystrophin was successfully rescued with Pip6f-PMO in an organotypic mdx cerebellar culture. If mdx mice and DMD patients share similar neuropathogenesis, the development of drugs targeting the altered functions in mdx Purkinje cells may serve as a potential therapy in alleviating the cognitive impairments seen in DMD.
... To evaluate the role of Nav1.6 in the inflammatory response during EAE, we used Scn8a dmu/+ , which are heterozygous for a null allele of Scn8a and express low levels of Scn8a, the gene that encodes the alpha subunit of Nav1.6. The heterozygous mice that had a single mutation in Nav1.6 resulting in a decreased expression of the channel protein did not show any overt neurological deficit; however, they presented with behavioral and emotional changes (47). It has been reported that Nav1.2 compensates for partial reductions of Nav1.6 in heterozygous mice indicating that Nav1.6 is unable to fully occupy the nodal membrane, which allows Nav1.2 to function and stabilize at the node of Ranvier. ...
Voltage gated sodium (Nav) channels contribute to axonal damage following demyelination in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). The Nav1.6 isoform has been implicated as a primary contributor in this process. However, the role of Nav1.6 in immune processes, critical to the pathology of both MS and EAE, has not been extensively studied. EAE was induced with myelin oligodendrocyte (MOG35-55) peptide in Scn8admu/+ mice, which have reduced Nav1.6 levels. Scn8admu/+ mice demonstrated improved motor capacity during the recovery and early chronic phases of EAE relative to wild-type animals. In the optic nerve, myeloid cell infiltration and the effects of EAE on the axonal ultrastructure were also significantly reduced in Scn8admu/+ mice. Analysis of innate immune parameters revealed reduced plasma IL-6 levels and decreased percentages of Gr-1high/CD11b⁺ and Gr-1int/CD11b⁺ myeloid cells in the blood during the chronic phase of EAE in Scn8admu/+ mice. Elevated levels of the anti-inflammatory cytokines IL-10, IL-13, and TGF-β1 were also observed in the brains of untreated Scn8admu/+ mice. A lipopolysaccharide (LPS) model was used to further evaluate inflammatory responses. Scn8admu/+ mice displayed reduced inflammation in response to LPS challenge. To further evaluate if this was an immune cell-intrinsic difference or the result of changes in the immune or hormonal environment, mast cells were derived from the bone marrow of Scn8admu/+ mice. These mast cells also produced lower levels of IL-6, in response to LPS, compared with those from wild type mice. Our results demonstrate that in addition to its recognized impact on axonal damage, Nav1.6 impacts multiple aspects of the innate inflammatory response.
... Mutations in mouse Na v 1.6 have been associated with ataxia, muscle weakness, tremor, dystonia and juvenile lethality [32,46,47], and conditional deletion of Scn8a in mouse cerebellar neurons resulted in mild ataxia [48]. However, it was not until the mid-2000s that the first human mutation in SCN8A was found in a patient with mental retardation, ataxia and cerebellar atrophy [49]. ...
Voltage gated sodium channels (Nav) play a crucial role in action potential initiation and propagation. Although the discovery of Nav channels dates back more than 65 years, and great advances in understanding their localization, biophysical properties, and links to disease have been made, there are still many questions to be answered regarding the cellular and molecular mechanisms involved in Nav channel trafficking, localization and regulation. This review summarizes the different trafficking mechanisms underlying the polarized Nav channel localization in neurons, with an emphasis on the axon initial segment (AIS), as well as discussing the latest advances regarding how neurons regulate their excitability by modifying AIS length and location. The importance of Nav channel localization is emphasized by the relationship between mutations, impaired trafficking and disease. While this review focuses on Nav1.6, other Nav isoforms are also discussed.
... Very recently, however, a case report implicating a gain-of-function mutation of NaV1.6 in exacerbating trigeminal neuralgia has been reported (47). Homozygous SCN8A null mice exhibit motor defects including ataxia, dystonia, paralysis and tremor, and do not survive beyond 3 weeks (40,(48)(49)(50), but do not exhibit not sensory defects. NaV1.6 regulates neuronal excitability via three properties: its subcellular localization at the axon initial segment (AIS), the site of initiation of action potentials, and at the nodes of Ranvier; its role in persistent and resurgent current; and the voltage-dependence of its activation (12,46). ...
... In contrast, most Nav1.6 mutations are recessive. An allelic mutation A107T in DIII S4-S5 caused ataxic phenotype by shifting Nav1.6 activation and inactivation to about 14 mV in the depolarizing direction, suggesting Nav1.6 is required for the complex spiking of cerebellar Purkinje cells and for persistent sodium current in several classes of neurons [91][92][93]. ...
