Loss of the neuronal kinase DCLK3 leads to anxiety-like behaviour and memory deficits

Abstract 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.