Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods

Abstract

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file;Source Data file has been provided for Figure 1.Source Code files have been provided for Figure 6 and for Figure 6 - Figure supplement 1.

Article and author information

Author details

  1. Eduardo Loureiro-Campos

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  2. António Mateus-Pinheiro

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  3. Patrícia Patrício

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  4. Carina Soares-Cunha

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  5. Joana Silva

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  6. Vanessa Morais Sardinha

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  7. Bárbara Mendes-Pinheiro

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  8. Tiago Silveira-Rosa

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6159-1623
  9. Ana Verónica Domingues

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  10. Ana João Rodrigues

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1968-7968
  11. João Oliveira

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1005-2328
  12. Nuno Sousa

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  13. Nuno Dinis Alves

    Department of Psychiatry, Columbia University Medical Center, New York, United States
    For correspondence
    nda2114@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Luísa Pinto

    Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
    For correspondence
    luisapinto@med.uminho.pt
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7724-0446

Funding

Fundação para a Ciência e a Tecnologia (SFRH/BD/131278/2017)

  • Eduardo Loureiro-Campos

Fundação para a Ciência e a Tecnologia (UIDB/50026/2020 and UIDP/50026/2020)

  • Eduardo Loureiro-Campos
  • António Mateus-Pinheiro
  • Joana Silva
  • Vanessa Morais Sardinha
  • Bárbara Mendes-Pinheiro
  • Tiago Silveira-Rosa
  • Ana Verónica Domingues
  • Ana João Rodrigues
  • João Oliveira
  • Nuno Sousa
  • Luísa Pinto

Fundação para a Ciência e a Tecnologia (PPBI-POCI-01-0145-FEDER-022122)

  • Eduardo Loureiro-Campos
  • António Mateus-Pinheiro
  • Joana Silva
  • Vanessa Morais Sardinha
  • Bárbara Mendes-Pinheiro
  • Tiago Silveira-Rosa
  • Ana Verónica Domingues
  • Ana João Rodrigues
  • João Oliveira
  • Nuno Sousa
  • Luísa Pinto

Fundação para a Ciência e a Tecnologia (SRFH/BD/120124/2016)

  • Bárbara Mendes-Pinheiro

Fundação para a Ciência e a Tecnologia (SFRH/BD/135273/2017)

  • Tiago Silveira-Rosa

Fundação para a Ciência e a Tecnologia (SFRH/BD/147066/2019)

  • Ana Verónica Domingues

Fundação para a Ciência e a Tecnologia (CEECIND/03887/2017)

  • Carina Soares-Cunha

Fundação para a Ciência e a Tecnologia (IF/00328/2015,IF/01079/2014; PTDC/MED-NEU/31417/2017)

  • João Oliveira

Fundação para a Ciência e a Tecnologia (2020.02855.CEECIND)

  • Luísa Pinto

Fundação Bial (037/18)

  • João Oliveira

Fundação Bial (427/14)

  • Luísa Pinto

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

Ethics

Animal experimentation: Efforts were made to minimize the number of animals and their suffering. All experimental procedures performed in this work were conducted in accordance with the EU Directive 2010/63/EU and approved by the Portuguese National Authority for animal experimentation, Direção-Geral de Alimentação e Veterinária (DGAV) with the project reference 0420/000/000/2011 (DGAV 4542).

Reviewing Editor

  1. D Nora Abrous, Neurocentre Magendie, INSERM, France

Publication history

  1. Received: May 26, 2021
  2. Preprint posted: June 8, 2021 (view preprint)
  3. Accepted: December 2, 2021
  4. Accepted Manuscript published: December 3, 2021 (version 1)
  5. Version of Record published: December 24, 2021 (version 2)

Copyright

© 2021, Loureiro-Campos 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. Eduardo Loureiro-Campos
  2. António Mateus-Pinheiro
  3. Patrícia Patrício
  4. Carina Soares-Cunha
  5. Joana Silva
  6. Vanessa Morais Sardinha
  7. Bárbara Mendes-Pinheiro
  8. Tiago Silveira-Rosa
  9. Ana Verónica Domingues
  10. Ana João Rodrigues
  11. João Oliveira
  12. Nuno Sousa
  13. Nuno Dinis Alves
  14. Luísa Pinto
(2021)
Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods
eLife 10:e70685.
https://doi.org/10.7554/eLife.70685

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