Biology subjects

Glasscock, E.

Publications and source records attributed to Glasscock, E..

3 recordsLinked to original sources

bioRxiv2025

Cardiac-specific Kv1.1 deficiency alters cardiomyocyte electrophysiology without modifying overall cardiac function or arrhythmia 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 -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, cKOs 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.

physiology↗

bioRxiv2025

EGR3 Deletion Rescues Developmental and Epileptic Encephalopathy in Kcna1-null Mice

KCNA1 encodes the -subunit of the voltage-gated potassium channel KV1.1. Mutations in KV1.1s pore domain result in developmental and epileptic encephalopathy (DEE), where early life seizures and a culprit lesion synergistically disrupt neurodevelopmental trajectories, resulting in intellectual disability that often presents with disturbances in sleep, sociability and sensory processing. Abnormalities in the subcellular localization of Kv1.1, via mutations in/autoantibodies against LGI1 and CNTNAP2, also give rise to syndromes of epilepsy and neuropsychiatric impairment. Mice with deletions of Kcna1("-/-") display spontaneous seizures at 2-3 weeks of age and premature mortality. In this study, we applied instrumented home-cage monitoring to examine how aberrations in KCNA1 expression may result in pervasive alterations in spontaneous behavior. Compared to wildtype, Kcna1-/- mice displayed a robust multifaceted behavioral syndrome featuring marked nocturnal hyperactivity, insomnia, reduced sheltering, fragmented feeding/drinking rhythms, sensory over-responsivity and diminished wheel-running. In identical recordings, Kcna1+/- mice only displayed increased sheltering, Lgi1+/- mice displayed mild insomnia and Cntnap2-/- mice showed home-cage hypoactivity. Kcna1 loss in parvalbumin-positive interneurons (Pv-Cre) resulted in a subtle phenocopy, with mild insomnia accompanied by reduced sheltering behavior, while similar deletions in forebrain pyramidal neurons (Emx1-Cre) or dopaminergic neurons (DAT-Cre) were asymptomatic. Adult-onset conditional deletions of Kcna1 also produced only mild insomnia 6 weeks later. To survey the molecular landscape in Kcna1-/- mice, we conducted a mass spectrometry proteomic analysis of dissected hippocampal tissue (a predominant seizure onset zone and where astrogliosis is observed). This revealed significant upregulations in BDNF (brain-derived neurotrophic factor) and the immediate early transcription factor EGR3 (early growth response-3), which is necessary for the induction of BDNF following electroconvulsive seizures. Heterozygous or homozygous deletions of Egr3 in Kcna1-/- mice resulted in significant survival prolongation, a partial neurobehavioral rescue, and a significant improvement in the frequency of spontaneous seizures and spreading depolarization events. These clinical improvements were associated with an amelioration of BDNF induction, hippocampal astrogliosis and proteomic disturbances. Together, these data illustrate how an ion channel that governs excitability at millisecond scales also shapes the spatiotemporal structure of spontaneous behavior at meso- or macroscopic time scales. Our results provide a model and a set of precision endpoints to understand how ictal and interictal features of DEE may be ameliorated by inhibiting the long-term downstream transcriptional alterations imparted by early life seizures.

neuroscience↗

bioRxiv2021

Kv1.1 subunits localize to cardiorespiratory brain networks in mice where their absence induces astrogliosis and microgliosis

Cardiorespiratory collapse following a seizure is a suspected cause of sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. In the commonly used Kcna1 gene knockout (Kcna1-/-) mouse model of SUDEP, cardiorespiratory profiling reveals an array of aberrant breathing patterns that could contribute to risk of seizure-related mortality. However, the brain structures mediating these respiratory abnormalities remain unknown. We hypothesize that Kv1.1 deficiency in respiratory control centers of the brain contribute to respiratory dysfunction in Kcna1-/- mice leading to increased SUDEP risk. Thus, in this study, we first used immunohistochemistry to map expression of Kv1.1 protein in cardiorespiratory brain regions of wild-type Kcna1+/+ (WT) mice. Next, GFAP and Iba1 immunostaining was used to test for the presence of astrogliosis and microgliosis, respectively, in the cardiorespiratory centers of Kcna1-/- mice, which could be indicative of seizure-related brain injury that could impair breathing. In WT type mice, we detected Kv1.1 protein in all cardiorespiratory centers examined, including the basolateral amygdala, dorsal respiratory group, dorsal motor nucleus of vagus, nucleus ambiguus, ventral respiratory column, and pontine respiratory group, as well as chemosensory centers including the retrotrapezoid and median raphae nuclei. Extensive gliosis was observed in the same areas in Kcna1-/- mice suggesting that seizure-associated brain injury could contribute to respiratory abnormalities.

neuroscience↗