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Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S‐licarbazepine; S‐lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain‐of‐function (G1475R and M1760I) and one variant with biophysical gain‐of‐function but neuronal loss‐of‐function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6‐associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S‐lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S‐lic exhibits variant‐specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant‐associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S‐lic. Conclusions and Implications: S‐lic has not only substance‐specific effects but also variant‐specific effects. Personalized treatment regimens optimized to achieve such variant‐specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A‐related disease. [ABSTRACT FROM AUTHOR]

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization. [ABSTRACT FROM AUTHOR]

Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]

Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]

A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism. [ABSTRACT FROM AUTHOR]

Missense mutations in SCN2A, encoding the brain sodium channel NaV1.2, have been described in benign familial neonatal-infantile seizures ( BFNIS), a self-limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography ( EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of NaV1.2 (D4/S2-S3). Functional studies using heterologous expression in tsA201 cells and whole-cell patch clamping revealed a depolarizing shift of steady-state inactivation, increased persistent Na+ current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain-of-function. Using an action potential waveform in a voltage-clamp experiment we indicated an increased inward Na+ current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome. [ABSTRACT FROM AUTHOR]

Proprioceptive sensory feedback has important functions for motor pattern generation in which phasic negative and positive feedback is used to coordinate neural and musculoskeletal dynamics. Whether and how feedback sign regulates the motor patterns in behaviorally relevant closed-loop conditions has not been fully elucidated. We characterized the feedback provided by the anterior gastric receptor (AGR), a muscle tendon organ in the stomatogastric nervous system of the crab Cancer pagurus, to the gastric mill motor pattern in intact animals. AGR innervates the protractor muscles and was activated either during the protraction or retraction phase of the rhythm. Experiments with neuromuscular preparations imply that this was due to isometric contractions of the protractor muscles and their passive stretch by the antagonistic retractor muscles. As AGR excited the protractors and inhibited the retractors independently of the timing of its activation, the timing switch changed AGR feedback from positive to negative. We tested the effects of this change in feedback sign on the motor pattern in the isolated nervous system by activating AGR at the corresponding phases of the rhythm, using intracellular current injection. When AGR was activated during the protractor phase and provided positive feedback, it prolonged the burst activities of protractor and retractor neurons and slowed ongoing rhythms. When activated during the retraction phase and thus provided negative feedback, burst durations decreased and the rhythm cycle frequency increased. Our study thus shows that the cycle frequency of centrally generated activity patterns can be regulated by switching the sign of phasic proprioceptive feedback. [ABSTRACT FROM AUTHOR]

The gas nitric oxide (NO) serves a diversity of functions in the nervous system and plays an important role in the modulation of oscillatory networks. We investigated the actions of intrinsically produced NO on the rhythmically active gastric mill circuit within the stomatogastric ganglion (STG) of the crab,Cancer pagurus. Bath application of different NO blockers exclusively to the STG terminated spontaneously active gastric mill rhythms. Furthermore, a reduction in the activity levels of projection neurons that sustain the gastric mill rhythm was observed, suggesting that NO blockade influences feedback mechanisms that affect projection neuron activity. When STG feedback to these projection neurons was intact, their activity decreased strongly with NO blockers present exclusively in the STG. When either neuronal feedback was eliminated or projection neurons were tonically activated, NO blockade did not terminate the gastric mill rhythm, indicating an indirect ascending control of the projection neurons. Together, our results show that ascending feedback from a motor network is important in shaping network activity and that this feedback is state-dependent and can be modulated to alter the output of the motor network. [ABSTRACT FROM AUTHOR]

A response from authors of an article related to the role of potassium voltage-gated channel subfamily A member 2 (KCNA2) phenotypes in causing hereditary spastic paraplegia and ataxia, which was published in a previous issue of the periodical is presented.