Identifying the Role of Molecular Drivers of Seizure-induced Neurogenesis
Abstract number :
3.004
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2024
Submission ID :
329
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Marissa Coppin, BS – University of Texas at San Antonio
Presenting Author: Diana Perez, BS – University of Texas at San Antonio
adebayo adeyeye, MS – University of Texas at San Antonio
Nico Enerlan, BS – University of Texas at San Antonio
Jenny Hsieh, PhD – University of Texas at San Antonio
Rationale: Seizure-induced aberrant hippocampal neurogenesis significantly contributes to chronic seizure development. Previous studies in our lab revealed that 2-week-old (2w) adult-born granule cells (abGCs) in the mouse dentate gyrus show elevated Ca2+ activity following pilocarpine (pilo)-induced seizures. This heightened Ca2+ activity, which can be mitigated through chemogenetic DREADDs/hM4Di silencing, suggests a role in aberrant neurogenesis and epileptogenesis. However, the molecular mechanisms by which elevated Ca2+ activity drives these processes remain unclear. Given the differential expression of genes like Timp3 and RRM2 in abGCs following seizures and their known roles in cellular processes, we hypothesized that these genes mediate aberrant neurogenesis through altered Ca2+-mediated gene expression.
Methods: Given Timp3’s known role in regulating migration and invasion of tumor cells, we hypothesized that seizure-induced changes in Timp3 expression could influence aberrant abGC migration. To investigate Timp3’s role in aberrant abGC development, we used the LXR agonist T0901317, which is reported to knock down Timp3 expression. Similarly, RRM2’s known role is to regulate the cell cycle and upregulation of this gene is associated with increased proliferation of cancer cells. To investigate RRM2’s role, we used a similar small molecule knockdown approach, we used 3-AP to knockdown RRM2.
Results: In wildtype mice, treatment with T0901317 resulted in an increased number of hilar ectopic immature neurons, with no changes in migration of abGCs or granule cell dispersion. Alternatively, treatment with 3AP resulted in a reduction of ectopic abGCs and seizure activity in pilo-treated mice.
Conclusions: These findings suggest that alterations in Ca2+ activity within 2w-old abGCs post-pilo treatment lead to changes in gene expression, including Timp3 and RRM2. Knockdown of Timp3 enhances immature neuron migration, while knockdown of RRM2 seems to more directly alter neurogenesis, rescuing the aberrant activity of these newborn neurons. This work highlights a novel approach to manipulating potential aberrant gene regulatory pathways and underscores the functional roles of both Timp3 and RRM2 in aberrant abGC neurogenesis.
Funding: This work was supported by the National Institutes of Health (R01NS124855 to J.H.) and an AES BRIDGE internship grant to D.P.
Basic Mechanisms