Retinal electrical synapse plasticity is required for optimal visual performance

Lin, Y.-P.; Mitchell, C. K.; Jin, N.; Tetenborg, S.; Brantley, N. A.; Zhang, Z.; Naglis, A.; Long, Y.; Li, H.; Luke, S.; Mao, C.-A.; Wang, S. W.; Ribelayga, C. P.; O'Brien, J.

doi:10.64898/2026.07.27.741000

bioRxiv · 10.64898/2026.07.27.741000

Retinal electrical synapse plasticity is required for optimal visual performance

Lin, Y.-P.·Mitchell, C. K.·Jin, N.·Tetenborg, S.·Brantley, N. A.·Zhang, Z.·Naglis, A.·Long, Y.·Li, H.·Luke, S.·Mao, C.-A.·Wang, S. W.·Ribelayga, C. P.·O'Brien, J.

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Abstract

Most electrical synapses in the mammalian central nervous system are composed of Connexin 36 (Cx36). Electrical synapses are functionally plastic, changing their degree of coupling based on the activity of the cell or connected cells, or based on activation of neurotransmitter or neurohormone receptors. Plasticity can reach an extreme in which electrical synapses become functionally silent, which is a normal operational condition for some circuits. Cx36 coupling is regulated by phosphorylation, which opens the channels. In retinal circuits, Cx36 is often maintained in a poorly phosphorylated, poorly coupled state. We reasoned that phosphomimetic mutants of Cx36 could remain constitutively open and maintain circuits in a well-coupled state that will interrogate the need for plasticity. We developed a constitutively open Cx36 mutant by systematically replacing phosphorylatable residues that regulate coupling with acidic residues. Single mutants of serine 315 significantly modified functional regulation of coupling in HeLa cells, but mutation of four residues was required to produce a mutant that was constitutively open. This mutant, Cx36-S110D, T111E, S293D, S315D, called Cx36-DEDD, displayed high coupling in control conditions and only modest changes under phosphorylating and dephosphorylating conditions. We developed a conditional knockin mouse that expresses Cx36-DEDD and cytoplasmic tdTomato in cells that expressed Cre recombinase. When crossed with Six3-Cre mice, Cx36-DEDD expressed widely in the retina including in photoreceptors, bipolar, amacrine and ganglion cells. Rod-cone electrical coupling displayed the maximum of its physiological dynamic range, and photopic visual acuity and contrast sensitivity were significantly reduced in Cx36-DEDD homozygous animals. We conclude that reduction of coupling in some retinal circuits is required for optimal daylight vision. Significance StatementTwo types of synapses, chemical and electrical, work together throughout the central nervous system to perform neurological functions. While it is widely understood for chemical synapses that plasticity, changing the strength of synaptic connections, plays critical roles in many processes, this is far less understood for electrical synapses. By developing an electrical synapse protein mutant that locks channels in an open state, we have investigated retinal circuits that retain functional electrical synapses but lack their latitude for plasticity. This perturbation significantly compromises visual acuity and contrast sensitivity in the daylight, revealing that electrical synapse plasticity is necessary to tune retinal functions for optimal performance. Thus, electrical synapse plasticity along with chemical synapse plasticity is required for neural function.

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Lin, Y.-P., Mitchell, C. K., Jin, N., Tetenborg, S., Brantley, N. A., Zhang, Z., Naglis, A., Long, Y., Li, H., Luke, S., Mao, C.-A., Wang, S. W., Ribelayga, C. P., O'Brien, J.. 2026-07-28. Retinal electrical synapse plasticity is required for optimal visual performance. https://doi.org/10.64898/2026.07.27.741000

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