Epilepsy is a neurologic disorder that effects between 1-4% of the population and is associated with significant morbidity and even mortality. The birth of new neurons and astrocytes (cellular proliferation) is a unique and central pathologic process that occurs in the hippocampus of patients with epilepsy that likely contributes to epileptogenesis and may be accentuated by recurrent seizures. The genes that regulate cell proliferation in epilepsy have not been identified and understanding why cell proliferation occurs in epilepsy will yield insight into seizure initiation in select patients. Indeed, the molecular pharmacologic phenotype of new cells may be distinct from existing hippocampal astrocytes and neurons ad thus, may provide critical changes in receptor or ion channel expression that fosters seizure initiation. Thus, one term goal of the proposed studies is to identify select cell populations in epilepsy that can be targeted for cell specific therapeutic modulation. The objective of this proposal is to study the molecular basis of neuronal and glial proliferation in human epilepsy and to define the molecular pharmacologic phenotype of newly born neurons and astrocytes. The goals of our proposal match well with the mission statement of the RFA and provide an intensive plan to investigate the mechanisms that modulate cellular proliferation in epilepsy. To accomplish these goals, we will assay cellular proliferation in a well-characterized rodent seizure model system and then in human epilepsy samples. The experiments in the proposal will: 1) identify select populations of newly divided neurons and astrocytes in the dentate gyrus by BrdU and immunohistochemical approaches, 2) determine the electrophysiologic properties of these proliferating cells so they can be readily identified in human epilepsy samples, 3) use a targeted strategy to define altered expression of several candidate gene families in experimental and human epilepsy, and 4) corroborate the changes in gene expression with protein assays including Western analysis and immunohistochemistry.
| Sosunov, Alexander A; Wu, Xiaoping; Weiner, Howard L et al. (2008) Tuberous sclerosis: a primary pathology of astrocytes? Epilepsia 49 Suppl 2:53-62 |
| Samadani, Uzma; Judkins, Alexander R; Akpalu, Albert et al. (2007) Differential cellular gene expression in ganglioglioma. Epilepsia 48:646-53 |
| Crino, Peter B (2004) Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol 19:716-25 |
