ZEISS at Society for Neuroscience (SfN) 2026

Abstract

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge debris is unknown. Here, we explore whether pathogenic autoantibodies

found in MS induce microglial phagocytic myelin destruction. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and binding of Fc gamma receptor and complement. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Bruton’s tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.  

Abstract:

Although retinal circuits have long been studied by volumetric electron microscopy (McGuire et al., 1984; Famiglietti et al., 1991; Anderson et al., 2011), no comprehensive wiring diagram has emerged. Eyewire II spans a 1 × 1 × 0.09 mm³ volume of mouse retina with ~100,000 neurons, ≳10× larger in area than previous datasets (Briggman et al., 2011; Helmstaedter et al., 2013; Ding et al., 2016). Unlike Eyewire I (Briggman et al., 2011; Kim et al., 2014; Bae et al., 2018), conventional staining reveals synapses. Before fixation, we electroporated the explanted retina with a calcium indicator (Briggman and Euler, 2011) and recorded light responses, including to natural movies, of 380 ganglion cell layer somata in five 90 × 90 µm fields (~40,000 µm²). After heavy-metal staining and resin embedding, ~4,000 45-nm sections were cut. So far, 2,064 have been imaged at nanometer resolution on a Zeiss Merlin scanning electron microscope, covering all synaptic layers. Researchers and citizen scientists proofread the machine-learning segmentation, reconstructing over 37,000 neurons. More than 120 retina researchers worldwide use the data, making Eyewire II a growing community resource toward a complete retinal connectome.