Loss of the neuronal kinase DCLK3 leads to anxiety-like behaviour and memory deficits
DCLK3 (Doublecortin-like kinase 3) is a kinase preferentially expressed in neurons. Dclk3 variants are risk factors for psychiatric disorders and brain alterations linked to age-related mild cognitive impairment, suggesting that this kinase could be important to cognition. However, the physiological role of DCLK3 remains unknown. Here, we generated and characterized mice with constitutive or brain region-specific Dclk3 knockout. We found that constitutive pan-deletion of Dclk3 is associated with an anxiety phenotype in males, associated with changes in brain metabolites in the absence of major neuroanatomical alterations, motor deficits or memory deficits. Moreover, virally mediated loco-regional conditional Dclk3 knockout in the dorsal hippocampus of adult mice led to spatial memory deficits and transcriptomic changes, characterized by increased expression of α2, β1 and β2 subunits of the GABAA receptor, downregulation of neuronal activity-regulated genes, such as the immediate early genes (e.g. Egr1, Fos, Per1 and Nr4r1), and transcriptional regulator activity enriched in polycomb-repressive complexes. These new data reveal that Dclk3 modulates behaviour and cognition in association with transcriptomic changes in the hippocampus, providing direct physiological evidence that this kinase is involved in synaptic plasticity, consistent with its crucial role in neurodegenerative and psychiatric diseases.
Authors
- Marc Dhénain (ORCID: https://orcid.org/0000-0001-8804-4101)
- Julien Flament (ORCID: https://orcid.org/0000-0002-6412-3427)
- Karine Cambon (ORCID: https://orcid.org/0000-0001-9263-4366)
- Gilles Bonvento (ORCID: https://orcid.org/0000-0002-2886-4228)
- Martine Guillermier
- Fabien Bertaux (ORCID: https://orcid.org/0009-0004-2098-3988)
- Christian Néri (ORCID: https://orcid.org/0000-0002-3790-2978)
- Nachiket A. Nadkarni
- Caroline Jan
- Julien Mitja
- Charles Decraene (ORCID: https://orcid.org/0000-0001-7682-4987)
- Céline Keime (ORCID: https://orcid.org/0000-0001-7604-3814)
- J. Pérot (ORCID: https://orcid.org/0000-0002-6066-2909)
- Alexis‐Pierre Bemelmans (ORCID: https://orcid.org/0000-0001-7605-5225)
- Lucie de Longprez (ORCID: https://orcid.org/0000-0001-7350-4742)
- Emmanuel Brouillet (ORCID: https://orcid.org/0000-0001-6322-7403)
- Marie‐Claude Gaillard
- Philippe Hantraye
- Géraldine Liot (ORCID: https://orcid.org/0000-0002-4784-7693)
- Karine Mérienne (ORCID: https://orcid.org/0000-0003-2549-2315)
- Mathilde Louçã
- Gwennaëlle Aurégan
- Marie Norbert
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Centre Hospitalier Universitaire Vaudois (CH)
- Sorbonne Université (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Centre National pour la Recherche Scientifique et Technique (CNRST) (MA)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Genoway (France) (FR)
- Institut de Biologie Paris-Seine (FR)
- Laboratoire de Neurosciences Cognitives et Adaptatives (FR)
- Institut National de Santé Publique (TN)
- Université de Strasbourg (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- Brain
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1093/brain/awaf042
- Citations
- 5
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- Agence Nationale de la Recherche
- Université Paris-Saclay