GABAA presynaptic inhibition regulates the gain and kinetics of retinal output neurons

  1. Jenna Nagy
  2. Briana Ebbinghaus
  3. Mrinalini Hoon
  4. Raunak Sinha  Is a corresponding author
  1. University of Wisconsin, United States

Abstract

Output signals of neural circuits, including the retina, are shaped by a combination of excitatory and inhibitory signals. Inhibitory signals can act presynaptically on axon terminals to control neurotransmitter release and regulate circuit function. However, it has been difficult to study the role of presynaptic inhibition in most neural circuits due to lack of cell-type specific and receptor-type specific perturbations. In this study, we used a transgenic approach to selectively eliminate GABAA inhibitory receptors from select types of second order neurons - bipolar cells - in mouse retina and examined how this affects the light response properties of the well-characterized ON alpha ganglion cell retinal circuit. Selective loss of GABAA receptor-mediated presynaptic inhibition causes an enhanced sensitivity and slower kinetics of light-evoked responses from ON alpha ganglion cells thus highlighting the role of presynaptic inhibition in gain control and temporal filtering of sensory signals in a key neural circuit in the mammalian retina.

Data availability

All source data shown in the figures including some raw data are available in the data repository, Dryad, accessible via this link https://doi.org/10.5061/dryad.bg79cnpb4. Raw datasets are quite large in size and will be made available upon request by the corresponding author.

The following data sets were generated

Article and author information

Author details

  1. Jenna Nagy

    Neuroscience, University of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Briana Ebbinghaus

    Department of Ophthalmology, University of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mrinalini Hoon

    Department of Neuroscience, University of Wisconsin, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Raunak Sinha

    Department of Neuroscience, University of Wisconsin, Madison, United States
    For correspondence
    raunak.sinha@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7553-1274

Funding

National Eye Institute (EY026070)

  • Raunak Sinha

McPherson Eye Research Institute (David and Nancy Walsh Family Professorship in Vision Research)

  • Raunak Sinha

McPherson Eye Research Institute (Rebecca Brown Professorship in Vision Research)

  • Mrinalini Hoon

Research to Prevent Blindness

  • Mrinalini Hoon

National Institute of General Medical Sciences (T32 Graduate Student Fellowship)

  • Jenna Nagy

National Eye Institute (EY031677)

  • Mrinalini Hoon

National Institute of Neurological Disorders and Stroke (T32NS105602)

  • Briana Ebbinghaus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Marla B Feller, University of California, Berkeley, United States

Ethics

Animal experimentation: All experiments and animal care were conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) of the University of Wisconsin-Madison and the National Institutes of Health. The protocol was approved by the Animal Care and Use Committee of the University of Wisconsin-Madison (Protocol ID: M006031-R01).

Version history

  1. Received: July 13, 2020
  2. Accepted: April 6, 2021
  3. Accepted Manuscript published: April 27, 2021 (version 1)
  4. Version of Record published: May 10, 2021 (version 2)
  5. Version of Record updated: May 13, 2021 (version 3)

Copyright

© 2021, Nagy et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,791
    Page views
  • 186
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jenna Nagy
  2. Briana Ebbinghaus
  3. Mrinalini Hoon
  4. Raunak Sinha
(2021)
GABAA presynaptic inhibition regulates the gain and kinetics of retinal output neurons
eLife 10:e60994.
https://doi.org/10.7554/eLife.60994

Share this article

https://doi.org/10.7554/eLife.60994

Further reading

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

    1. Medicine
    2. Neuroscience
    Luisa Fassi, Shachar Hochman ... Roi Cohen Kadosh
    Research Article

    In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual’s subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants’ subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.