title: Accumulation of abnormal adult-generated hippocampal granule cells predicts seizure frequency and severity.
abstract: Accumulation of abnormally integrated, adult-born, hippocampal dentate granule cells (DGCs) is hypothesized to contribute to the development of temporal lobe epilepsy (TLE). DGCs have long been implicated in TLE, because they regulate excitatory signaling through the hippocampus and exhibit neuroplastic changes during epileptogenesis. Furthermore, DGCs are unusual in that they are continually generated throughout life, with aberrant integration of new cells underlying the majority of restructuring in the dentate during epileptogenesis. Although it is known that these abnormal networks promote abnormal neuronal firing and hyperexcitability, it has yet to be established whether they directly contribute to seizure generation. If abnormal DGCs do contribute, a reasonable prediction would be that the severity of epilepsy will be correlated with the number or load of abnormal DGCs. To test this prediction, we used a conditional, inducible transgenic mouse model to fate map adult-generated DGCs. Mossy cell loss, also implicated in epileptogenesis, was assessed as well. Transgenic mice rendered epileptic using the pilocarpine-status epilepticus model of epilepsy were monitored continuously by video/EEG for 4 weeks to determine seizure frequency and severity. Positive correlations were found between seizure frequency and (1) the percentage of hilar ectopic DGCs, (2) the amount of mossy fiber sprouting, and (3) the extent of mossy cell death. In addition, mossy fiber sprouting and mossy cell death were correlated with seizure severity. These studies provide correlative evidence in support of the hypothesis that abnormal DGCs contribute to the development of TLE and also support a role for mossy cell loss.
authors.affiliation: Department of Anesthesia and Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hester
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D000818:Animals; D064032:Calbindin 2; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins; D002452:Cell Count; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004965:Estrogen Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000473:pathology; D018721:Muscarinic Agonists / Q000633:toxicity; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D010862:Pilocarpine / Q000633:toxicity; D011237:Predictive Value of Tests; D018091:Receptors, AMPA / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D013629:Tamoxifen / Q000494:pharmacology; D014741:Video Recording; D000071676:Zinc Finger Protein GLI1
chemical_list: D064032:Calbindin 2; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D004965:Estrogen Antagonists; C498520:Gli1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D018721:Muscarinic Agonists; D018091:Receptors, AMPA; D064030:S100 Calcium Binding Protein G; C491177:Slc30a3 protein, mouse; D000071676:Zinc Finger Protein GLI1; C485184:enhanced green fluorescent protein; D010862:Pilocarpine; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; C104722:glutamate receptor ionotropic, AMPA 2