1. Neuroscience

A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity

  1. TD Barbara Nguyen-Vu  Is a corresponding author
  2. Grace Q Zhao
  3. Subhaneil Lahiri
  4. Rhea R Kimpo
  5. Hanmi Lee
  6. Surya Ganguli
  7. Carla J Shatz
  8. Jennifer L Raymond  Is a corresponding author
  1. Stanford School of Medicine, United States
https://doi.org/10.7554/eLife.20147
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Cite this article
  1. TD Barbara Nguyen-Vu
  2. Grace Q Zhao
  3. Subhaneil Lahiri
  4. Rhea R Kimpo
  5. Hanmi Lee
  6. Surya Ganguli
  7. Carla J Shatz
  8. Jennifer L Raymond
(2017)
A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity
eLife 6:e20147.
https://doi.org/10.7554/eLife.20147
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Abstract

Across many studies, animals with enhanced synaptic plasticity exhibit either enhanced or impaired learning, raising a conceptual puzzle: how enhanced plasticity can yield opposite learning outcomes? Here we show that recent history of experience can determine whether mice with enhanced plasticity exhibit enhanced or impaired learning in response to the same training. Mice with enhanced cerebellar LTD, due to double knockout (DKO) of MHCI H2-Kb/H2-Db (KbDb-/-), exhibited oculomotor learning deficits. However, the same mice exhibited enhanced learning after appropriate pre-training. Theoretical analysis revealed that synapses with history-dependent learning rules could recapitulate the data, and suggested that saturation may be a key factor limiting the ability of enhanced plasticity to enhance learning. Moreover, optogenetic stimulation designed to saturate LTD produced the same impairment in WT as observed in DKO mice. Overall, our results suggest that recent history of activity and the threshold for synaptic plasticity conspire to effect divergent learning outcomes.

Article and author information

Author details

  1. TD Barbara Nguyen-Vu

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    For correspondence
    ngbabs@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4708-1982

  2. Grace Q Zhao

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.

  3. Subhaneil Lahiri

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2028-6635

  4. Rhea R Kimpo

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.

  5. Hanmi Lee

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.

  6. Surya Ganguli

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.

  7. Carla J Shatz

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.

  8. Jennifer L Raymond

    Department of Neurobiology, Stanford School of Medicine, Stanford, United States
    For correspondence
    jenr@stanford.edu
    Competing interests
    Jennifer L Raymond, Reviewing editor, eLife.

Funding

National Institutes of Health (RO1DC04154,RO1NS072406,R21NS057488,P30DC10363)

  • Jennifer L Raymond

National Science Foundation (Graduate Research Fellowship)

  • TD Barbara Nguyen-Vu

Burroughs Wellcome Fund

  • Surya Ganguli

Genentech Foundation

  • Hanmi Lee

James S. McDonnell Foundation

  • Jennifer L Raymond

National Institutes of Health (F31DC010547)

  • TD Barbara Nguyen-Vu

National Institutes of Health (F32NS058060)

  • Grace Q Zhao

National Institutes of Health (RO1MH07166)

  • Carla J Shatz

National Institutes of Health (NS069375)

  • Jennifer L Raymond

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

Ethics

Animal experimentation: All experimental procedures were approved by the Administrative Panel on Laboratory Animal Care at Stanford University under animal care and use committee (IACUC) Protocol #9143, titled 'Vestibular and Visual Control of Eye Movements in Mice'.

Copyright

© 2017, Nguyen-Vu 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.

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  1. TD Barbara Nguyen-Vu
  2. Grace Q Zhao
  3. Subhaneil Lahiri
  4. Rhea R Kimpo
  5. Hanmi Lee
  6. Surya Ganguli
  7. Carla J Shatz
  8. Jennifer L Raymond
(2017)
A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity
eLife 6:e20147.
https://doi.org/10.7554/eLife.20147

Share this article

https://doi.org/10.7554/eLife.20147

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Further reading

    1. Neuroscience

    Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome

    Amin MD Shakhawat, Jacqueline G Foltz ... Jennifer L Raymond
    Research Advance

    The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb−/−), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb−/−mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.