1. Neuroscience
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Memory recall involves a transient break in excitatory-inhibitory balance

  1. Renée S Koolschijn  Is a corresponding author
  2. Anna Shpektor
  3. William T Clarke
  4. I Betina Ip
  5. David Dupret
  6. Uzay E Emir
  7. Helen C Barron  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. Purdue University, United States
Research Article
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Cite this article as: eLife 2021;10:e70071 doi: 10.7554/eLife.70071

Abstract

The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism.

Data availability

The data and code used in this study are available via the MRC BNDU Data Sharing PlatformThe data is available here:https://data.mrc.ox.ac.uk/data-set/fmri-fmrs-inferenceDOI: https://doi.org/10.5287/bodleian:vmJOOm7KDThe code is available here:https://data.mrc.ox.ac.uk/data-set/frms-codeDOI: https://doi.org/10.5287/bodleian:8JwYayQmD

Article and author information

Author details

  1. Renée S Koolschijn

    University of Oxford, Oxford, United Kingdom
    For correspondence
    renee.koolschijn@keble.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9553-4213
  2. Anna Shpektor

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. William T Clarke

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. I Betina Ip

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3544-0711
  5. David Dupret

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Uzay E Emir

    school of health science, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5376-0431
  7. Helen C Barron

    University of Oxford, Oxford, United Kingdom
    For correspondence
    helen.barron@merton.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Funding

Engineering and Physical Sciences Research Council (EP/L016052/1)

  • Renée S Koolschijn

Royal Society Dorothy Hodgkin Research Fellowship

  • I Betina Ip

Wellcome Trust (203836/Z/16/Z)

  • Anna Shpektor

Biotechnology and Biological Sciences Research Council (BB/N0059TX/1)

  • David Dupret

Medical Research Council (MC_UU_12024/3)

  • David Dupret

John Fell Fund, University of Oxford (153/046)

  • Helen C Barron

Wellcome Centre for Integrative Neuroimaging (Seed grant)

  • Helen C Barron

Merton College, University of Oxford (JRF)

  • Helen C Barron

Medical Research Council (MC_UU_12024/3)

  • Helen C Barron

Wellcome Trust (203139/Z/16/Z)

  • Renée S Koolschijn
  • Anna Shpektor
  • William T Clarke
  • I Betina Ip
  • Helen C Barron

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

Ethics

Human subjects: All participants gave informed written consent.All experiments were approved by the University of Oxford ethics committee (reference number R43594/RE001).

Reviewing Editor

  1. Muireann Irish, University of Sydney, Australia

Publication history

  1. Preprint posted: November 27, 2020 (view preprint)
  2. Received: May 5, 2021
  3. Accepted: September 7, 2021
  4. Accepted Manuscript published: October 8, 2021 (version 1)
  5. Version of Record published: October 14, 2021 (version 2)

Copyright

© 2021, Koolschijn 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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    The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.