title: PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure.
abstract: Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offsets the reduction in boutons per axon length. These morphological changes predict a net increase in granule cell innervation of CA3. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell communication with CA3. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Candi L
authors.initials: CL
authors.lastname: LaSarge
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Physiology, Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Santos
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Anesthesia, University of Cincinnati, Cincinnati, OH 45267, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address: steve.danzer@cchmc.org.
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008239:Lysine / Q000031:analogs & derivatives; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism* / Q000473:pathology*; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D056347:Neuroanatomical Tract-Tracing Techniques; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics
chemical_list: D049452:Green Fluorescent Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C013411:biocytin; D008239:Lysine
keywords: Dentate granule cells; Epilepsy; Hippocampus; Mossy fibers; PTEN; mTOR