title: Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy.
abstract: The dentate gyrus is hypothesized to function as a "gate," limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGCs) form aberrant neuronal connections with neighboring DGCs, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGCs in epilepsy has been known for decades, direct evidence linking abnormal DGCs to seizures has been lacking. Here, we isolate the effects of abnormal DGCs using a transgenic mouse model to selectively delete PTEN from postnatally generated DGCs. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGCs morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥ 9% of the DGC population developed spontaneous seizures in about 4 weeks, confirming that abnormal DGCs, which are present in both animals and humans with epilepsy, are capable of causing the disease.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Raymund Y K
authors.initials: RY
authors.lastname: Pun
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Rolle
authors.forename: Candi L
authors.initials: CL
authors.lastname: Lasarge
authors.forename: Bethany E
authors.initials: BE
authors.lastname: Hosford
authors.forename: Jules M
authors.initials: JM
authors.lastname: Rosen
authors.forename: Juli D
authors.initials: JD
authors.lastname: Uhl
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Schmeltzer
authors.forename: Christian
authors.initials: C
authors.lastname: Faulkner
authors.forename: Stefanie L
authors.initials: SL
authors.lastname: Bronson
authors.forename: Brian L
authors.initials: BL
authors.lastname: Murphy
authors.forename: David A
authors.initials: DA
authors.lastname: Richards
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Holland
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005911:Gliosis / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; 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; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009833:Olfactory Pathways / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D000071676:Zinc Finger Protein GLI1
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C498520:Gli1 protein, mouse; D007166:Immunosuppressive Agents; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D000071676:Zinc Finger Protein GLI1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051528:Guanylate Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D010751:Phosphopyruvate Hydratase; D020123:Sirolimus