AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS neurons.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative disorder caused by intronic biallelic, nonreference CCCTT/AAGGG repeat expansions within RFC1. To investigate how these repeats cause disease, we generated patient induced pluripotent stem cell-derived neurons (iNeurons). CCCTT/AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway function. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins. However, these proteins and repeat RNA foci were not detected in iNeurons, and overexpression of these repeats failed to induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded AAGGG allele. These deficits were neither replicated by RFC1 knockdown in control iNeurons nor rescued by RFC1 reprovision in CANVAS iNeurons. These findings support a repeat-dependent but RFC1 protein-independent cause of neuronal dysfunction in CANVAS, with implications for therapeutic development in this currently untreatable condition.

Immune Checkpoint Inhibitor-induced Bilateral Vestibulopathy.

Checkpoint inhibitors (CPI), such as anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4antibodies cause serious, rarely fatal immune-related adverse events (irAE) potentially in all organ systems. Neurological immune-related adverse events occur in 1%-5% of patients on CPI therapy and may present with dramatic clinical symptoms of the sensory organs. After exclusion of other causes, a high-dose treatment with corticosteroids is crucial for clinical outcome with lower risk of sequelae. We present a severe case of CPI-related ongoing and most likely irreversible bilateral vestibular affection. A 59-year-old male melanoma patient with brain metastasis undergoing immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies developed severe debilitating rotatory vertigo. Bilateral vestibulopathy was diagnosed as a result of the CPI therapy after a thorough analysis including magnetic resonance imaging, laboratory tests of blood and cerebrospinal fluid as well as neurological and otorhinolaryngology examinations. The vertigo improved slightly during a 10-day course of steroid therapy and intensive balance training but did not resolve completely.

Pathogenetic Role of Endothelial Dysfunction in Idiopathic Vestibulopathy.

Comparative analysis of the groups of patients with idiopathic bilateral vestibular hypofunction and a group of vestibulopathy patients with vertebrobasilar insufficiency demonstrated identity of the basic and additional diagnostic parameters in these syndromes as well as similarity in clinical diagnostic and anamnesis data. In all cases, functional assessment of endothelium-dependent vasodilation and selected biochemical marker sICAM-1 revealed endothelial dysfunction. Drug correction of endothelial dysfunction positively affected the manifestations of major and minor features of the syndrome, which confirmed the contribution of endothelial functional disturbances to the pathogenesis of bilateral vestibular hypofunction.

Hippocampal and striatal M1 -muscarinic acetylcholine receptors are down-regulated following bilateral vestibular loss in rats.

Permanent vestibular loss has detrimental effects on the hippocampus, resulting in a disruption to spatial learning and memory, hippocampal theta rhythm and place cell field spatial coherence. Little is known about the vestibular system-related hippocampal cholinergic transmission. Since the pharmacological blockade of muscarinic acetylcholine (ACh) receptors within the hippocampus produces deficits in learning and memory, we hypothesized that ACh receptors may at least partly support the integration of vestibular input. Consequently, we examined the expression of M1 muscarinic ACh receptors in the hippocampus at 7 and 30 days following bilateral vestibular lesions (BVL) in rats using autoradiography. Animals were divided into sham (n = 12) and BVL (n = 11) groups. BVL animals received intratympanic injections of sodium arsanilate (30 mg/0.1 ml) under isoflurane anesthesia and sham animals received the same volume of saline. Analysis of the brain tissue revealed a significant reduction in the number of M1 receptors throughout the hippocampus and striatum at 30 days (P ≤ 0.0001), but not at 7 days following BVL. This suggests that the changes in learning and memory seen following vestibular damage may be in part due to the loss of M1 muscarinic receptors in the hippocampus and striatum. © 2016 Wiley Periodicals, Inc.

Exploration of Circadian Rhythms in Patients with Bilateral Vestibular Loss.

BACKGROUND: New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants. METHODOLOGY AND PRINCIPAL FINDINGS: Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day. CONCLUSION: We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.