Biology subjects

Pahlberg, J.

Publications and source records attributed to Pahlberg, J..

4 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↗

bioRxiv2018

Activation of rod input in a in a model of retinal degeneration reverses retinal remodeling and induces formation of normal synapses, circuitry and visual signaling in the adult retina

A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells dissolve and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and is thought to occur in response to deafferentation. How the remodeled retinal circuit affect visual processing following rod rescue is not known. To address this question, we generated transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channel exhibit a resting membrane potential that was ~10mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.\n\nSignificance StatementCurrent strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neuron functions within a complex neural circuitry, which also becomes degraded during disease. It is not known whether a rescued neuron and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward rod bipolar cell dendrites re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.

neuroscience↗