HYBRID SYNAPSE FOR VISION RESTORATION

Photoreceptor degenerative diseases cause irreversible blindness despite survival of inner retinal neurons. Existing electrical retinal prostheses lack the spatial resolution and cellular specificity needed to restore ON and OFF cone pathways essential for contrast vision.
To overcome these limitations, we propose a hybrid chemical retinal prosthesis that integrates synaptic biomimicry to selectively activate surviving retinal circuits in response to light. The device consists of a silicon nitride membrane incorporating a basal glutamate reservoir and apical nanopores coated with a spiropyran polymer, enabling light-dependent glutamate release. The device surface is functionalized with glypican-4 (GPC4), a heparan sulfate proteoglycan whose HS chains selectively bind leucine-rich repeat transmembrane protein 4 (LRRTM4) expressed by ON-bipolar cells. Recombinant GPC4-HS, engineered with a sortase recognition tag, is conjugated to the surface via a thiol-terminated PEG linker, enabling its presentation as a presynaptic organizing cue that promotes synapse-like adhesion and functional coupling with surviving retinal circuits.
LRRTM4 functionality was validated by increased synaptic puncta in primary neurons co-expressing GluA1 and LRRTM4. GPC4-HS was produced and purified from overexpression in transfected cell lines. Double patch-clamp recordings in neuron/HEK293 co-cultures demonstrated glutamate-evoked currents in LRRTM4/GluA1-expressing HEK293 cells, supporting adhesion-driven hybrid synapse formation.
Translation to ex vivo and in vivo models will exploit endogenous LRRTM4 expression in BCs, spatially confining glutamate signaling to nanopore-BC junctions, minimizing extrasynaptic diffusion and enhancing spatial precision. This strategy combines molecular synaptic specificity with photochemical stimulation, offering a high-fidelity alternative to conventional electrical prostheses.