Biology subjects

Kramer, R. H.

Publications and source records attributed to Kramer, R. H..

5 recordsLinked to original sources

bioRxiv2026

The P2X7 receptor is an intermediate in the retinoic acid-signaling pathway that induces neuronal remodeling in retinitis pigmentosa

Photoreceptor degeneration drives electrophysiological remodeling in downstream retinal neurons, including hyperactive firing of retinal ganglion cells (RGCs) that degrades residual vision. Although Retinoic Acid (RA) and its receptor (RAR) are known to upregulate ion channel genes associated with RGC hyperactivity, these genes lack canonical RAR binding sites required for direct transcriptional regulation. Here, we identify P2X7 receptor (P2X7R) as a key intermediary in RA-induced remodeling in the rd1 mouse model of retinitis pigmentosa. Genetic deletion of P2X7R prevents the upregulation of RA-responsive genes and abolishes RGC hyperactivity. Loss of P2X7R also eliminates RGC hyperpermeability, as measured by uptake of an otherwise membrane-impermeant dye. Acute pharmacological inhibition of P2X7R suppresses hyperpermeability without affecting hyperactivity, supporting an indirect signaling mechanism rather than a direct electrophysiological role. Notably, elevation of resting Ca{superscript 2} is absent in P2X7R-deficient cells, implicating Ca{superscript 2}-dependent gene expression as a link between P2X7R-mediated hyperpermeability and RGC hyperactivity. Together, these findings establish P2X7R as a critical intermediate in retinal remodeling and a potential therapeutic target for preserving vision in retinitis pigmentosa. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/728267v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@7745d4org.highwire.dtl.DTLVardef@89a01corg.highwire.dtl.DTLVardef@16ea51borg.highwire.dtl.DTLVardef@119d0f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Retinal bipolar cells borrow excitability from electrically coupled inhibitory interneurons to amplify excitatory synaptic transmission

Bipolar cells (BCs) carry visual information from photoreceptors in the outer retina to retinal ganglion cells (RGCs) in the inner retina. Most BCs lack voltage-gated Na+ (NaV) channels and action potentials. Instead, voltage signals spread passively from input to output synapses. Despite this, we find that blocking NaV channels reduces synaptic output of On-cone bipolar cells (On-CBCs). These cells borrow NaV channel-mediated excitability from electrically coupled A2 amacrine cells to amplify excitatory output, allowing voltage changes to be transmitted more effectively to downstream RGCs in dim light. Because neighboring On-CBCs form electrical synapses onto the same A2 cell, a spatially adjacent group of On-CBCs is more effective than a dispersed set for recruiting A2 cell electrical excitability and driving post-synaptic RGCs. This mechanism filters the neural representation of an image to highlight shapes over spatially uncorrelated stimuli, a sophisticated feature detection property that is well-suited for object recognition.

neuroscience↗

bioRxiv2021

Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration

In degenerative retinal disorders, rod and cone photoreceptors die, causing vision impairment and blindness. Downstream neurons survive but undergo morphological and physiological remodeling, with some retinal ganglion cells (RGC) exhibiting heightened spontaneous firing. Retinoic acid (RA) has been implicated as the key signaling molecule that induces RGC hyperactivity, obscuring RGC light responses and reducing light avoidance behaviors triggered by residual rods and cones. However, evidence that RA-dependent remodeling corrupts image-forming vision has been lacking. Here we show that disulfiram, an FDA-approved drug that inhibits RA synthesis, and BMS 493, an RA receptor (RAR) inhibitor, reduce RGC hyperactivity and augment image detection in visually impaired mice. Functional imaging of visual cortical neurons shows that disulfiram and BMS 493 sharpen orientation-tuning and strengthen response fidelity to naturalistic scenes. These findings establish a causal link between RA-induced retinal hyperactivity and vision impairment and define molecular targets and candidate drugs for boosting image-forming vision in retinal degeneration.

neuroscience↗

bioRxiv2020

FeRIC-based magnetogenetics: evaluation of methods and protocols in in vitro models

FeRIC (Ferritin iron Redistribution to Ion Channels) is a magnetogenetic technique that uses radio frequency (RF) alternating magnetic fields to activate the transient receptor potential channels, TRPV1 and TRPV4, coupled to cellular ferritins. In cells expressing ferritin-tagged TRPV, RF stimulation increases the cytosolic Ca2+ levels via a biochemical pathway. The interaction between RF and ferritin increases the free cytosolic iron levels that in turn, trigger chemical reactions producing reactive oxygen species and oxidized lipids that activate the ferritin-tagged TRPV. In this pathway, it is expected that experimental factors that disturb the ferritin expression, the ferritin iron load, the TRPV functional expression, or the cellular redox state will impact the efficiency of RF in activating ferritin-tagged TRPV. Here, we examined several experimental factors that either enhance or abolish the RF control of ferritin-tagged TRPV. The findings may help optimize and establish reproducible magnetogenetic protocols.

bioengineering↗

bioRxiv2018

Somatic nicotinic acetylcholine receptors control the activity of dopamine neurons and reward-related behaviors.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in vivo. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through somatic {beta}2-containing ({beta}2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

neuroscience↗