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The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype–phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype–phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Background Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Previous studies have shown that Scn2a+/– ameliorates epilepsy in Kcna1–/– mice, improving survival, seizure characteristics, and brain–heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD‐like repetitive and social behaviors in Scn2a+/– mice. Methods Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. Results Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1–/– mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1+/–) exhibited increased self‐grooming and decreased sociability suggestive of ASD‐like features similar to those observed in Scn2a+/– mice. In double‐mutant Scn2a+/–; Kcna1+/– mice, the two mutations interacted to partially normalize ASD‐like behaviors associated with each mutation independently. Conclusions Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD. This work investigates how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Behavioral testing revealed altered repetitive and social behaviors in mice dependent on whether the Kcna1 gene was partially or completely knocked out. In double‐mutant Scn2a+/–; Kcna1+/– mice, the two mutations interacted to partially rescue ASD‐like behaviors associated with each mutation independently, suggesting that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD.

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel's pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Implanted gradient index lenses have extended the reach of standard multiphoton microscopy from the upper layers of the mouse cortex to the lower cortical layers and even subcortical regions. These lenses have the clarity to visualize dynamic activities, such as calcium transients, with subcellular and millisecond resolution and the stability to facilitate repeated imaging over weeks and months. In addition, behavioral tests can be used to correlate performance with observed changes in network function and structure that occur over time. Yet, this raises the questions, does an implanted microlens have an effect on behavioral tests, and if so, what is the extent of the effect? To answer these questions, we compared the performance of three groups of mice in three common behavioral tests. A gradient index lens was implanted in the prefrontal cortex of experimental mice. We compared their performance with mice that had either a cranial window or a sham surgery. Three presurgical and five postsurgical sets of behavioral tests were performed over seven weeks. Behavioral tests included rotarod, foot fault, and Morris water maze. No significant differences were found between the three groups, suggesting that microlens implantation did not affect performance. The results for the current study clear the way for combining behavioral studies with gradient index lens imaging in the prefrontal cortex, and potentially other regions of the mouse brain, to study structural, functional, and behavioral relationships in the brain.

Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy.

RNA-binding proteins play critical roles in regulation of gene expression, and impairment can have severe phenotypic consequences on nervous system function. We report here the discovery of several complex neurological phenotypes associated with mutations of couch potato (cpo), which encodes a Drosophila RNA-binding protein. We show that mutation of cpo leads to bang-sensitive paralysis, seizure susceptibility, and synaptic transmission defects. A new cpo allele called cpoEG1 was identified on the basis of a bang-sensitive paralytic mutant phenotype in a sensitized genetic background (sda/+). In heteroallelic combinations with other cpo alleles, cpoEG1 shows an incompletely penetrant bang-sensitive phenotype with ∼30% of flies becoming paralyzed. In response to electroconvulsive shock, heteroallelic combinations with cpoEG1 exhibit seizure thresholds less than half that of wild-type flies. Finally, cpo flies display several neurocircuit abnormalities in the giant fiber (GF) system. The TTM muscles of cpo mutants exhibit long latency responses coupled with decreased following frequency. DLM muscles in cpo mutants show drastic reductions in following frequency despite exhibiting normal latency relationships. The labile sites appear to be the electrochemical GF-TTMn synapse and the chemical PSI-DLMn synapses. These complex neurological phenotypes of cpo mutants support an important role for cpo in regulating proper nervous system function, including seizure susceptibility.

The leading cause of epilepsy‐related mortality is sudden unexpected death in epilepsy (SUDEP), resulting from seizure‐induced cardiorespiratory arrest by mechanisms that remain unresolved. Mutations in ion channel genes expressed in both brain and heart represent SUDEP risk factors because they can disrupt neural and cardiac rhythms, providing a unified explanation for seizures and lethal arrhythmias. However, the relative contributions of brain‐driven mechanisms, heart‐intrinsic processes and seizures to cardiac dysfunction in epilepsy remain unclear. Here, we investigated the heart‐specific role of the Kcna1 gene, which encodes Kv1.1 voltage‐gated potassium channel α‐subunits expressed in both neurons and cardiomyocytes, where they shape action potential firing and influence seizure and arrhythmia susceptibility. We generated cardiac‐specific Kcna1 conditional knockout (cKO) mice lacking Kv1.1 selectively in cardiomyocytes and assessed their cardiac function using in vitro and in vivo electrophysiology. Cardiac Kv1.1 deficiency prolonged action potentials in atrial, but not ventricular, cardiomyocytes, demonstrating a direct role for Kv1.1 in atrial repolarization. Despite these cellular effects, cKO mice exhibited normal lifespans, electrocardiographic features, heart rate variability, pacing‐induced arrhythmia susceptibility, contractility, seizure susceptibility and seizure‐induced mortality. Thus, while loss of cardiac Kv1.1 was sufficient to impair atrial repolarization, it did not reproduce the broader cardiac abnormalities seen in global Kcna1 knockouts. Given the higher mortality rates of global compared with neural‐specific knockouts in our previous studies, cardiac Kv1.1 deficiency, while not lethal alone, may increase vulnerability to seizure‐related death when combined with neural deficiency, consistent with a brain–heart dyssynergy that lowers the threshold for fatal events. What is the central question of the study? Does loss of Kv1.1 potassium channel subunits in the heart alone cause the cardiac dysfunction and susceptibility to seizure‐related death seen in the Kv1.1 knockout mouse model of sudden unexpected death in epilepsy (SUDEP), or are these abnormalities primarily driven by the brain? What is the main finding and its importance? Cardiac‐specific Kv1.1 deletion prolongs atrial action potentials, revealing a role in atrial repolarization, but does not substantially affect lifespan, overall cardiac performance or seizure‐induced mortality. Thus, cardiac Kv1.1 loss alone is not particularly harmful but may increase vulnerability to seizure‐related death when combined with neural deficiency, indicating a brain–heart dyssynergy in SUDEP.

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897–914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel Kv1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al., eLife 10, e58779 (2021)]. To assess the role of Kv1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove Kv1.1 from adult neural stem cells via tamoxifen administration. We determined that Kv1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.

Despite decades of research on adult neurogenesis, little is known about the role of bioelectric signaling in this process. In this study, we describe how a voltage-gated potassium channel, K v 1.1, supports adult neurogenesis by maintaining the neural stem cell niche and facilitating newborn neuron development. Additionally, we show that deletion of K v 1.1 from adult neural stem cells contributes to modest impairments in hippocampus-dependent contextual fear learning and memory. Dysfunctional adult neurogenesis has been implicated in cognitive decline associated with aging and neurological disease. Therefore, understanding the role of K v 1.1 in adult neurogenesis represents an opportunity to identify new therapeutic targets to promote healthy neurogenesis and cognition. Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897–914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel K v 1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al. , eLife 10, e58779 (2021)]. To assess the role of K v 1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove K v 1.1 from adult neural stem cells via tamoxifen administration. We determined that K v 1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.

Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1 -null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1 -null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson’s trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.