Kundishora, A. J. | bioRxiv Science

bioRxiv2023

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗

bioRxiv2021

Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

neuroscience↗