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PKCδ-positive GABAergic neurons in the central amygdala exhibit tissue-type plasminogen activator: role in the control of anxiety

Molecular Psychiatry volume 27, pages 2197–2205 (2022)Cite this article

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Abstract

Tissue plasminogen activator (tPA) is a serine protease expressed in several brain regions and reported to be involved in the control of emotional and cognitive functions. Nevertheless, little is known about the structure-function relationships of these tPA-dependent behaviors. Here, by using a new model of constitutive tPA-deficient mice (tPAnull), we first show that tPA controls locomotor activity, spatial cognition and anxiety. To investigate the brain structures involved in these tPA-dependent behavioral phenotypes, we next generated tPAflox mice allowing conditional tPA deletion (cKO) following stereotaxic injections of adeno-associated virus driving Cre-recombinase expression (AAV-Cre-GFP). We demonstrate that tPA removal in the dentate gyrus of the hippocampus induces hyperactivity and partial spatial memory deficits. Moreover, the deletion of tPA in the central nucleus of the amygdala, but not in the basolateral nucleus, induces hyperactivity and reduced anxiety-like level. Importantly, we prove that these behaviors depend on the tPA present in the adult brain and not on neurodevelopmental disorders. Also, interestingly, our data show that tPA from Protein kinase-C delta-positive (PKCδ) GABAergic interneurons of the lateral/ capsular part of adult mouse central amygdala controls emotional functions through neuronal activation of the medial central amygdala. Together, our study brings new data about the critical central role of tPA in behavioral modulations in adult mice.

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Fig. 1: Constitutive tPA-deficient mice (tPAnull) display locomotor, emotional and cognitive deficits.
Fig. 2: Conditional deletion of tPA in the hippocampus (cKO-DG) leads to locomotor hyperactivity and moderate spatial cognitive deficits.
Fig. 3: Conditional deletion of tPA in the central amygdala (cKO-CeA) leads to locomotor hyperactivity and reduced anxiety.
Fig. 4: Conditional deletion of tPA in the basolateral amygdala (cKO-BLA) does not affect locomotor, emotional or cognitive performance.
Fig. 5: tPA expressed in CeL/C PKCδ interneurons influences neuronal activation of the CeM.

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Acknowledgements

We are grateful to the molecular biology and viral production facility of MIRCen, François Jacob Institute of Biology, CEA for viral particles production. We thank Pr Gilles Bonvento for the help to setup the experimental guidelines regarding AAV manipulations. This work was supported by grants from the Ministère de l’Enseignement Supérieur et de la Recherche and INSERM (French National Institute for Health and Medical Research) (HCERES U1237-2017/2022).

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  1. These authors contributed equally: Véronique Agin, Denis Vivien.

Authors and Affiliations

  1. Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @ Caen-Normandie (BB@C), GIP Cyceron, 14000, Caen, France

    Sara Douceau, Eloïse Lemarchand, Yannick Hommet, Laurent Lebouvier, Eric Maubert, Véronique Agin & Denis Vivien

  2. Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurodégénératives, 92265, Fontenay-aux-Roses, France

    Charlène Joséphine & Alexis-Pierre Bemelmans

  3. Department of Clinical Research, Caen-Normandie University Hospital, CHU, Avenue de la côte de Nacre, Caen, France

    Denis Vivien

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Contributions

DV and VA designed and supervised the study. SD, EL, and DV performed the data analysis. SD, EL, YH, LL, and EM performed the experiments. AB and CJ designed and produced AAV constructs. SD, VA, and DV wrote the manuscript. All authors have read and have approved the final manuscript.

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Correspondence to Denis Vivien.

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Douceau, S., Lemarchand, E., Hommet, Y. et al. PKCδ-positive GABAergic neurons in the central amygdala exhibit tissue-type plasminogen activator: role in the control of anxiety. Mol Psychiatry 27, 2197–2205 (2022). https://doi.org/10.1038/s41380-022-01455-4

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