Molecular control of aberrant adult-born granule cells in epilepsy

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Project Summary/Abstract: The latent period after a severe brain insult such as traumatic brain injury or status epilepticus, and before the onset of spontaneous recurrent seizures, is characterized by changes in adult hippocampal neurogenesis. Profound morphological changes, including hilar ectopic granule cells and abnormal dendritic development (e.g., hilar basal dendrites) is observed, therefore raising the question whether seizure- induced neurogenesis is epileptogenic. Our past work of ablating adult neurogenesis before or after acute seizures has shown a pro- epileptic role of new neurons, however existing ablation strategies in animal models have all suffered from an inability to decipher the mechanisms that promote aberrant adult-born granule cells (abGCs) because the cells are removed from the circuit. In this revised R01 application, we will capitalize on recently published work from our laboratory demonstrating that activity in immature abGCs regulates Ca2+ and gene expression which is necessary and sufficient for the production of aberrant abGCs and disruption of the hippocampal circuitry leading to epilepsy. We propose work to determine the mechanisms that promote aberrant neurogenesis, focusing on the genes and signaling pathways that drive aberrant abGCs as well as identifying the neuronal inputs to the aberrant abGCs. Because our past work has always been in the pilocarpine model of mesial temporal lobe epilepsy, we will expand these studies to address the role of aberrant abGCs in a non-status model, such as epilepsy that occurs after controlled cortical impact injury. In Aim 1, we will demonstrate that hM4Di-regulated gene expression in abGCs offers a new way to manipulate potential aberrant gene regulatory pathways and define the functional role of our top 2 candidate genes – Timp3 and Rrm2 - identified in RNA- sequencing analysis. In Aim 2, we will complement the work in Aim 1 using hM4Di in the pilocarpine model and identify the hM3Dq activated genes and neuronal inputs associated with aberrant abGCs in wild-type mice. In Aim 3, we will ablate or silence abGCs after controlled cortical impact injury and evaluate the impact on the development of chronic seizures. Together these studies are expected to provide a greater understanding of the mechanisms that promote aberrant abGC maturation, which may offer new strategies to specifically target abnormal new neurons while sparing healthy neurons. These studies would be broadly impactful in a variety of neurological disorders including epilepsy.