The role of Doublecortin-like kinase 1 (DCLK1) in epilepsy progression

McCarthy-Sinclair, Brendan

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Year:: 2024
Contributor:: McCarthy-Sinclair, Brendan (creator); Botterill, Justin (Reader); de Graffenried, Chris (Advisor); Morrow, Eric (Advisor); Jaworski, Alex (Advisor); Liu, Judy (Advisor); Brown University. Department of Molecular Biology, Cell Biology and Biochemistry (sponsor)
Genre:: theses
Subject:: Epilepsy; Neuroscience
Extent:: 16, 114 p.

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Abstract:: Epilepsy is a complex neurological disorder characterized by recurrent seizures, affecting millions worldwide. Understanding the molecular mechanisms underlying epilepsy pathogenesis is crucial for developing effective therapeutic strategies. Cytoskeletal genes play critical roles in maintaining neuronal structure and function, and dysregulation of these genes has been implicated in epilepsy. Doublecortin-like kinase 1 (DCLK1), a member of the doublecortin family, exhibits diverse functions in the brain, including neuronal migration, dendritic spine development, and synaptic plasticity. In this study, we investigated the role of DCLK1 in pilocarpine-induced epilepsy both in wild-type mice and in a DCLK1 knockout mouse model. Through targeted deletion of the DCLK1 gene, we assessed its impact on seizure susceptibility and various hallmarks of epilepsy. We employed a combination of behavioral, electrophysiological, and molecular approaches to characterize the phenotype of epileptic DCLK1 knockout mice and elucidate the molecular pathways altered in its absence. Our findings reveal significant alterations in the epilepsy phenotype in epileptic DCLK1 knockout mice compared to epileptic wild-type controls. We first found DCLK1 expression is greatly increased in epileptic mice compared to healthy mice, independently of DCX. Knockout of DCLK1 resulted in increased mortality from pilocarpine-induced SE, and greater acute hippocampal cell death in the hippocampus. Epileptic DCLK1 knockout mice also had lower cell counts for both PV+ and SST+ inhibitory interneurons in the hippocampus. Timm staining of the hippocampus showed increases in mossy fiber sprouting in epileptic DCLK1 knockout mice compared to epileptic wild-type mice. Furthermore, EEG recordings revealed an increase in interictal epileptiform discharges during sleep and an increased seizure occurrence in the epileptic DCLK1 knockout mice. This led to significant changes in sleep architecture and maintenance. Our study provides compelling evidence for a previously uninvestigated involvement of DCLK1 in epilepsy and highlights its multifaceted roles in regulating neuronal circuitry and excitability. Understanding the mechanisms by which DCLK1 contributes to epilepsy pathogenesis may offer novel therapeutic targets for the treatment of this debilitating disorder.
Notes:: Thesis (Ph. D.)--Brown University, 2024

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Citation

McCarthy-Sinclair, Brendan, "The role of Doublecortin-like kinase 1 (DCLK1) in epilepsy progression" (2024). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:tm75asqn/

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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