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AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior

Molecular Psychiatry volume 22, pages 1725–1734 (2017)Cite this article

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Abstract

Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ (AP2γ, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2γ in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2γ-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2γ deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain.

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Acknowledgements

We acknowledge the excellent technical expertise of Luís Martins and Andrea Steiner-Mezzadri. We would also like to acknowledge Magdalena Götz for the insightful comments on the paper. AMP, PP, ARS, JS, VMS, NDA and JFO received fellowships from the Portuguese Foundation for Science and Technology (FCT). LP received fellowship from FCT and her work is funded by FCT (IF/01079/2014) and Bial Foundation (427/14) projects. This work was cofunded by the Life and Health Sciences Research Institute (ICVS), and Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038.

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Author notes

  1. A Mateus-Pinheiro and N D Alves: These authors contributed equally to this work.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    A Mateus-Pinheiro, N D Alves, P Patrício, A R Machado-Santos, E Loureiro-Campos, J M Silva, V M Sardinha, J Reis, J F Oliveira, N Sousa & L Pinto

  2. Life and Health Sciences Research Institute (ICVS)/3B’s—PT Government Associate Laboratory, Guimarães, Portugal

    A Mateus-Pinheiro, N D Alves, P Patrício, A R Machado-Santos, E Loureiro-Campos, J M Silva, V M Sardinha, J Reis, J F Oliveira, N Sousa & L Pinto

  3. Department of Developmental Pathology, Institute for Pathology, University of Bonn Medical School, Bonn, Germany

    H Schorle

  4. Institute for Stem Cell Research, Helmholtz Centre Munich German Research Center for Environmental Health (GmbH), Neuherberg, Germany

    J Ninkovic

  5. Physiological Genomics, Medical Faculty, University of Munich, Munich, Germany

    J Ninkovic

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  1. A Mateus-Pinheiro
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Correspondence to L Pinto.

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Mateus-Pinheiro, A., Alves, N., Patrício, P. et al. AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior. Mol Psychiatry 22, 1725–1734 (2017). https://doi.org/10.1038/mp.2016.169

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