title: Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis.
abstract: OBJECTIVE
  Aberrant plastic changes among adult-generated hippocampal dentate granule cells are hypothesized to contribute to the development of temporal lobe epilepsy. Changes include formation of basal dendrites projecting into the dentate hilus. Innervation of these processes by granule cell mossy fiber axons leads to the creation of recurrent excitatory circuits within the dentate. The destabilizing effect of these recurrent circuits may contribute to hyperexcitability and seizures. Although basal dendrites have been identified in status epilepticus models of epilepsy associated with increased neurogenesis, we do not know whether similar changes are present in the intrahippocampal kainic acid model of epilepsy, which is associated with reduced neurogenesis.
  
  
  METHODS
  In the present study, we used Thy1-YFP-expressing transgenic mice to determine whether hippocampal dentate granule cells develop hilar-projecting basal dendrites in the intrahippocampal kainic acid model. Brain sections were examined 2 weeks after treatment. Tissue was also examined using ZnT-3 immunostaining for granule cell mossy fiber terminals to assess recurrent connectivity. Adult neurogenesis was assessed using the proliferative marker Ki-67 and the immature granule cell marker calretinin.
  
  
  RESULTS
  Significant numbers of cells with basal dendrites were found in this model, but their structure was distinct from basal dendrites seen in other epilepsy models, often ending in complex tufts of short branches and spines. Even more unusual, a subset of cells with basal dendrites had an inverted appearance; they completely lacked apical dendrites. Spines on basal dendrites were found to be apposed to ZnT-3 immunoreactive puncta, suggestive of recurrent mossy fiber input. Finally, YFP-expressing abnormal granule cells did not colocalize Ki-67 or calretinin, indicating that these cells were more than a few weeks old, but were found almost exclusively in proximity to the neurogenic subgranular zone, where the youngest granule cells are located.
  
  
  CONCLUSIONS
  Recent studies have demonstrated in other models of epilepsy that dentate pathology develops following the aberrant integration of immature, adult-generated granule cells. Given these findings, one might predict that the intrahippocampal kainic acid model of epilepsy, which is associated with a dramatic reduction in adult neurogenesis, would not exhibit these changes. Herein we demonstrate that hilar basal dendrites are a common feature of this model, with the abnormal cells likely resulting from the disruption of juvenile granule cell born in the weeks before the insult. These studies demonstrate that postinjury neurogenesis is not required for the accumulation of large numbers of abnormal granule cells.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, U.S.A.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Murphy
authors.forename: Rylon D
authors.initials: RD
authors.lastname: Hofacer
authors.forename: Christian N
authors.initials: CN
authors.lastname: Faulkner
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Loepke
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D064032:Calbindin 2; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins; D002452:Cell Count; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology*; D007839:Functional Laterality; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007608:Kainic Acid / Q000009:adverse effects; D019394:Ki-67 Antigen / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019599:Mossy Fibers, Hippocampal / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D019394:Ki-67 Antigen; D008164:Luminescent Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D064030:S100 Calcium Binding Protein G; C491177:Slc30a3 protein, mouse; C054562:yellow fluorescent protein, Bacteria; D010751:Phosphopyruvate Hydratase; D007608:Kainic Acid