Biology subjects

Bocchero, U.

Publications and source records attributed to Bocchero, U..

3 recordsLinked to original sources

bioRxiv2026

Continuous Rod Noise and Nonlinear Synaptic Filtering Shape Signal Detection in the Primary Rod Pathway

Rod photoreceptors are optimized to detect single photons, but their performance near absolute visual threshold is limited by intrinsic phototransduction noise. The two major components are discrete single-photon-like events and continuous fluctuations in outer-segment current. Although spontaneous rhodopsin activation is established as the source of discrete noise, the molecular origin of continuous noise remains controversial, and how these distinct noise sources influence signal processing at the first visual synapse is not fully understood. To address these questions, we combined genetic manipulation of rhodopsin, phosphodiesterase 6 (PDE6), and glutamic acid rich protein 2 (GARP2) with single-cell recordings from rods and rod-bipolar cells (RBCs) and pharmacological manipulation of mGluR6 signaling. Continuous noise was unaffected by reduced rhodopsin concentration but was strongly influenced by PDE6 expression and regulation, supporting basal PDE6 activity as a major source of continuous noise. Reducing either discrete or continuous noise increased signal-to-noise ratio (SNR) in rods, but these changes were differentially processed at the rod-to-RBC synapse. In WT retina, the nonlinear transformation increased SNR, whereas elevated continuous noise limited this increase. Conversely, reduced continuous noise increased rod SNR, which was maintained in RBCs and associated with a lower detection threshold. Pharmacological reduction of the mGluR6-dependent nonlinearity altered these genotype-dependent differences, indicating that nonlinear filtering is well matched to normal signal and noise distributions but does not fully compensate when presynaptic noise is experimentally altered. Together, our study identifies spontaneous PDE6 activity as a major source of continuous noise and demonstrates that continuous noise interacts with nonlinear processing at the first visual synapse to determine the fidelity and detection threshold of dim-light signals.

neuroscience↗

bioRxiv2025

Selective Knockout of Murine Glutamic Acid-rich Protein 2 (GARP2) Significantly Alters Cellular Dark Noise in Rod Photoreceptors

GARP2, a glutamic-acid-rich protein found exclusively in rod photoreceptors, has been suggested to function as a structural protein, a modulator of the cGMP phosphodiesterase enzyme (PDE6), and a gating inhibitor of the rod cGMP-gated cation channel. GARP2 is a splice variant of the Cngb1 gene, which in the rods encodes the {beta}-subunit of the cyclic nucleotide-gated cation channel. Mutations in Cngb1 cause retinitis pigmentosa (RP45), and {beta}-subunit knockout mice are being studied as models of this disease. In this study, using ZFN-mediated gene editing, we have selectively eliminated GARP2 expression, while not affecting expression of the cyclic nucleotide gated cation channel {beta} -subunit, to determine its essential functions in mouse rods. The absence of GARP2 caused no consistent perturbations of retinal structure. Transiently, rod outer segment length was regionally greater than WT and infrequently misaligned, appearing parallel to the retinal pigment epithelium. Electroretinography of the knockout mice did reveal consistent functional alterations over time, seen as a reduction in the ERG response amplitudes in older mice, albeit with no significant alterations in sensitivity to light. Interestingly, single-cell patch-clamp recordings showed a significant reduction in rod photoreceptor dark noise consistent with a previously proposed role for GARP2 in binding to PDE6 and affecting its basal activity. Our results suggest a role for the GARP2-PDE6 interaction in stabilizing the PDE6 enzyme and controlling the turnover rate of cGMP in darkness, adjusting the level of dark noise and implicating an influence on the signal and noise properties of rod photoreceptors. Key PointsO_LIGlutamic acid-rich protein 2 (GARP2), an alternatively spliced variant of the Cngb1 gene, is exclusively expressed in rod photoreceptors, but the in vivo role of GARP2 remains unestablished. C_LIO_LIWe used precision gene editing technology to selectively knockout soluble GARP2 expression in rods, to determine its essential functions in structure and function of the retina. C_LIO_LIWe show that GARP2 has a minor role in maintaining the structural integrity of the rod outer segments as a function of age. C_LIO_LIOur study indicates that GARP2 has an important role in regulating rod photoreceptor dark noise, likely through stabilization of PDE6 basal activity to maintain the appropriate cGMP turnover rate. C_LIO_LIThis regulation is critical to facilitate the single-photon sensitivity and function of the rod photoreceptors. C_LI

neuroscience↗

bioRxiv2020

Retinal circuits driving a non-image forming visual behavior

Outer retinal circuits that drive non-image forming vision in mammals are unknown. Rods and cones signal light increments and decrements to the brain through the ON and OFF pathways, respectively. Although their contribution to image-forming vision is known, the contributions of the ON and OFF pathway to the pupillary light response (PLR), a non-image forming behavior, are unexplored. Here we use genetically modified mouse lines, to comprehensively define the outer retinal circuits driving the PLR. The OFF pathway, which mirrors the ON pathway in image-forming vision, plays no role in the PLR. We found that rods use the primary rod pathway to drive the PLR at scotopic light levels. At photopic light levels, the primary and secondary rod pathways drive normal PLR. Importantly, we find that cones are unable to compensate for rods. Thus, retinal circuit dynamics allow rods to drive the PLR across a wide range of light intensities.

neuroscience↗