Neurophysiologic and Chronic Safety Testing of a Miniaturized Active Implanted Device with Integrated Electrodes for Bioelectronic Medicine Applications.

New dosing paradigms in bioelectronic medicine applications, such as low duty cycle stimulation of the vagus nerve to treat inflammatory disorders, enable architectural shifts in active implantable devices that benefit patients. Herein, we describe various features of the MicroRegulator (MR), an innovative neurostimulation system that includes a unique electrode-integrated implantable nerve stimulator. To verify efficient activation of neuronal targets within the vagus nerve, a geometric emulator of the MR (identical form and electrical contact properties as the clinical MR device) was tested in situ and neurophysiologic outcomes were compared to a control electrode in wide clinical use. The data demonstrated comparable patterns of compound potentials evoked from the MR emulator and the control electrode, with the MR emulator requiring a lower threshold current to depolarize the nerve. To verify chronic mechanical safety, the MR emulator was implanted for 2 months on the vagus nerves of canines. Blood flow through the major cervical vessels was unaffected, and pathologic and histologic findings included normal foreign body encapsulation and an absence of demyelination and nerve damage. Together these finding support the feasibility of the MR system for clinical translation.

UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease.

UBE3A is an E3 ubiquitin ligase encoded by an imprinted gene whose maternal deletion or duplication leads to distinct neurodevelopment disorders Angelman and Dup15q syndromes. Despite the known genetic basis of disease, how changes in copy number of a ubiquitin ligase gene can have widespread impact in early brain development is poorly understood. Previous studies have identified a wide array of UBE3A functions, interaction partners, and ubiquitin targets, but no central pathway fully explains its critical role in neurodevelopment. Here, we review recent UBE3A studies that have begun to investigate mechanistic, cellular pathways and the genome-wide impacts of alterations in UBE3A expression levels to gain broader insight into how UBE3A affects the developing brain. These studies have revealed that UBE3A is a multifunctional protein with important nuclear and cytoplasmic regulatory functions that impact proteasome function, Wnt signaling, circadian rhythms, imprinted gene networks, and chromatin. Synaptic functions of UBE3A interact with light exposures and mTOR signaling and are most critical in GABAergic neurons. Understanding the genome-wide influences of UBE3A will help uncover its role in early brain development and ultimately lead to identification of key therapeutic targets for UBE3A-related neurodevelopmental disorders.