Defocus coding and transcriptomic remodeling in the mouse myopic retina

The theory of visually guided ocular growth is well supported in explaining myopia, but how the retina senses focus versus defocus and converts the signaling into growth-modulating genetic signals remains unresolved. Using whole-cell recordings and single-cell RNA-seq in the mouse retina, we show that lateral inhibitory networks-horizontal cells in the outer retina, but not AII amacrine cells in the inner retina, respond to optical defocus. Dopaminergic amacrine cells (DACs) are maximally excited by focused images and increasingly inhibited by high blur, consistent with dopamine's anti-myopiagenic role. Single-cell RNA sequencing (scRNA-seq) revealed stable cell-class composition but coordinated, cell type-specific remodeling of gamma-aminobutyric acid (GABA)-ergic synapse and gap-junction pathways in lens-induced myopic (LIM) retinas. Consistent with a key role for retinal dopamine signaling, we found gene-level, cell-type-specific remodeling: Atf4 and Gnb5 were significantly upregulated in highly myopic retinas, whereas multiple dopamine-pathway components (Gnas, Camk2d, Prkca, Creb1, Plcb4, Drd2, and Drd1) were significantly downregulated. Together, our results support a general principle: neuromodulator-gated electrical coupling shapes computations for signal discrimination, and chronic sensory blur in LIM drives cross-level plasticity, from biophysical states to gene expression, that biases downstream coding and growth signals. Targeted manipulation of dopaminergic signaling may restore adaptive defocus encoding and slow myopic progression.NEW & NOTEWORTHY Using lens-induced myopia as a model of blurred vision, we show that retinal circuits adapt to defocus in a cell type-specific way. Horizontal cell network, but not AII amacrine cell networks, alter their responses, whereas dopaminergic amacrine cells undergo early biophysical changes followed by transcriptional remodeling of the dopamine pathway. This cross-level adaptation, from synapses to gene expression, supports robust vision under uncertainty and suggests dopaminergic signaling as a target to restore healthy defocus encoding.