Regulation of Postnatal Dentate Gyrus Neurogenesis and its Alteration inExperimental Epilepsy.

Neurogenesis;Epilepsy;Neurosciences;Health Sciences;Neuroscience

Kron, Michelle MarieTurner, David ;

University of Michigan

关键词: Neurogenesis;    Epilepsy;    Neurosciences;    Health Sciences;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/91485/mkron_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Medial temporal lobe epilepsy (mTLE) is a common, intractable epilepsy of unknown cause. In rodent mTLE, prolonged seizures, termed status epilepticus, stimulate neurogenesis, but many newborn dentate granule cells (DGCs) migrate and integrate aberrantly. We hypothesized that adult-born, rather than pre-existing, neurons contribute to epileptic pathology in the hippocampal dentate gyrus. Using the rat pilocarpine model, which recapitulates many human mTLE features, we tested our hypothesis by injecting green fluorescent protein-carrying retrovirus to label neural stem cells, or by killing dividing stem cells to suppress neurogenesis pre or post-epileptic injury. We found that an epilepsy-inciting injury differentially influences developing neurons depending upon their ages. Fully mature neurons at the time of injury are resistant, whereas developing neurons of differing maturities contribute to distinct, specific epileptic pathologies. To address the molecular underpinnings of this phenomenon, we investigated the Reelin pathway. Reelin is secreted into the extracellular matrix, binds its receptors and is internalized, leading to phosphorylation of disabled-1 (Dab1), an adaptor protein. Evidence implicates the Reelin/Dab1 pathway in DGC development, and mice with Reelin, Dab1, or Reelin receptor mutations have abnormalities similar to those in experimental mTLE. To better understand the role of Dab1 in neurogenesis, we suppressed Dab1 expression using a mouse line with conditional Dab1 knock-in alleles, or by injecting retroviral vector carrying a Dab1 shRNA into the adult rat dentate gyrus. In Dab1-conditional knock-in mice, Dab1 deletion led to aberrant DGC migration, impaired dendritic maturation and axonal disorganization. In rats, retroviral Dab1 shRNA delivery decreased dendritic arborization of DGCs and induced numerous labeled glia in the hilus and DGC layer that were not seen with control shRNA. Aberrant neurogenesis is a proposed cause of seizures and cognitive deficits common in mTLE, and this work supports an important role for Dab1 signaling in both neuronal migration, dendrite formation, and directing DGC progenitors to a neuronal fate.Taken together, these data suggest that neurons of distinct maturities contribute to specific epileptic abnormalities and that the Reelin/Dab1 pathway may underlie some of these aberrations. Correcting signaling of this pathway after epileptogenic insult may offer a novel strategy to prevent mTLE.