# Synaptic and circuit mechanisms of compensation following loss of cone inputs in themature mouse retina

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $402,708

## Abstract

There is a gap in knowledge of how loss of 50-80% of cone photoreceptors produces almost no change in visual
acuity or sensitivity. While contributions from cortex have been examined, those from retina have been
underappreciated. The long-term goal to understand how the retina functions robustly in the face of
photoreceptor death will generate transformative insights into how neural plasticity compensates for cell
death. Understanding this compensation is likely to lead to earlier diagnostics and more effective treatments.
The overall objective of this proposal is to elucidate the fundamental synaptic and circuit-level mechanisms
that allow the retina to function while compensating for photoreceptor death. This proposal focuses on the
well-characterized circuit of the ON sustained alpha ganglion cell in mouse retina, a strong model circuit with
identified cell types, maps of specific connections, accessibility to genetic manipulation, and quantifiable
structure and function. Following genetic ablation of 50-75% of cones in adult retina with the diphtheria toxin
receptor, these ganglion cells adjust receptive field structures and spike responses. The observations are
congruent with adaptation, which adjusts integration and gain for stimulus statistics, e.g., greater integration
and gain at lower light levels, or homeostatic plasticity, which involves remodeling circuitry or channel
expression. The central hypothesis is that the retina can compensate for cone loss via mechanisms of
adaptation and/or homeostatic plasticity that we will determine in two specific aims: (Aim 1) identify the
extent and sites of compensation within the retinal circuit following partial cone loss in the adult and (Aim 2)
determine the contributions of partial stimulation, mean adaptation and homeostatic plasticity to the retina's
reaction to cone loss. The results of the first aim will identify the structural and functional consequences of
cone loss on the direct excitatory pathway from cones to type 6 cone bipolar cells to ON alpha ganglion cells.
The results of the second aim will determine how adaptation, changes in excitatory and inhibitory circuits, and
intrinsic excitability contribute to changes in ganglion cell spatial and intensity encoding following partial cone
loss. The approach is innovative for the genetic control over cone ablation in mature retina, the stage at which
most human retinal diseases occur; functional and structural examination with cell-type specific resolution;
and focus on synaptic and circuit mechanisms underlying a well known discrepancy between photoreceptor
loss and visual function. The research is significant for (1) uncovering mechanisms that may mask visual
deficits in early stages of photoreceptor loss; (2) suggesting diagnostics that could detect earlier onset of
diseases causing cone loss; (3) establishing knowledge about the flexibility of a sensory circuit and how this
flexibility pertains to a surviving circuit; (4) providing dir...

## Key facts

- **NIH application ID:** 9849284
- **Project number:** 5R01EY029772-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Felice A Dunn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,708
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849284

## Citation

> US National Institutes of Health, RePORTER application 9849284, Synaptic and circuit mechanisms of compensation following loss of cone inputs in themature mouse retina (5R01EY029772-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849284. Licensed CC0.

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