PMID- 31377403
OWN - NLM
STAT- MEDLINE
DCOM- 20200228
LR  - 20211204
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 321
DP  - 2019 Nov
TI  - Impact of mTOR hyperactive neurons on the morphology and physiology of adjacent 
      neurons: Do PTEN KO cells make bad neighbors?
PG  - 113029
LID - S0014-4886(19)30178-5 [pii]
LID - 10.1016/j.expneurol.2019.113029 [doi]
AB  - Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is 
      associated with epilepsy, autism and brain growth abnormalities in humans. mTOR 
      hyperactivation often results from developmental somatic mutations, producing 
      genetic lesions and associated dysfunction in relatively restricted populations 
      of neurons. Disrupted brain regions, such as those observed in focal cortical 
      dysplasia, can contain a mix of normal and mutant cells. Mutant cells exhibit 
      robust anatomical and physiological changes. Less clear, however, is whether 
      adjacent, initially normal cells are affected by the presence of abnormal cells. 
      To explore this question, we used a conditional, inducible mouse model approach 
      to delete the mTOR negative regulator phosphatase and tensin homolog (PTEN) from 
      <1% to >30% of hippocampal dentate granule cells. We then examined the morphology 
      of PTEN-expressing granule cells located in the same dentate gyri as the knockout 
      (KO) cells. Despite the development of spontaneous seizures in higher KO animals, 
      and disease worsening with increasing age, the morphology and physiology of 
      PTEN-expressing cells was only modestly affected. PTEN-expressing cells had 
      smaller somas than cells from control animals, but other parameters were largely 
      unchanged. These findings contrast with the behavior of PTEN KO cells, which show 
      increasing dendritic extent with greater KO cell load. Together, the findings 
      indicate that genetically normal neurons can exhibit relatively stable morphology 
      and intrinsic physiology in the presence of nearby pathological neurons and 
      systemic disease.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - LaSarge, Candi L
AU  - LaSarge CL
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, United States of America; Center for Pediatric 
      Neuroscience, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 
      45229, United States of America.
FAU - Pun, Raymund Y K
AU  - Pun RYK
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, United States of America; Center for Pediatric 
      Neuroscience, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 
      45229, United States of America.
FAU - Gu, Zhiqing
AU  - Gu Z
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, United States of America; Department of Anesthesia, 
      Children's hospital of Shanghai, Shanghai 200062, China.
FAU - Santos, Victor R
AU  - Santos VR
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, United States of America; Department of Morphology, 
      Institute of Biological Sciences, Federal University of Minas Gerais, Belo 
      Horizonte, Brazil.
FAU - Danzer, Steve C
AU  - Danzer SC
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, United States of America; Departments of Anesthesia and 
      Pediatrics, University of Cincinnati, Cincinnati, OH 45267, United States of 
      America; Center for Pediatric Neuroscience, Cincinnati Children's Hospital 
      Medical Center, Cincinnati, OH 45229, United States of America. Electronic 
      address: steve.danzer@cchmc.org.
LA  - eng
GR  - F32 NS083239/NS/NINDS NIH HHS/United States
GR  - R01 NS062806/NS/NINDS NIH HHS/United States
GR  - R01 NS065020/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190801
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (Pten protein, mouse)
SB  - IM
MH  - Animals
MH  - Dentate Gyrus/*metabolism/*pathology
MH  - Epilepsy/genetics/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neurons/*metabolism/*pathology
MH  - PTEN Phosphohydrolase/*deficiency
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC6744293
MID - NIHMS1537162
OTO - NOTNLM
OT  - Dentate gate
OT  - Dentate granule cell
OT  - Neurolucida
OT  - PTEN
OT  - Soma area
OT  - Somatic hypertrophy
OT  - mTOR
COIS- Conflict of interest: The authors declare no competing financial interests.
EDAT- 2019/08/05 06:00
MHDA- 2020/02/29 06:00
PMCR- 2020/11/01
CRDT- 2019/08/05 06:00
PHST- 2019/04/30 00:00 [received]
PHST- 2019/07/23 00:00 [revised]
PHST- 2019/07/31 00:00 [accepted]
PHST- 2019/08/05 06:00 [pubmed]
PHST- 2020/02/29 06:00 [medline]
PHST- 2019/08/05 06:00 [entrez]
PHST- 2020/11/01 00:00 [pmc-release]
AID - S0014-4886(19)30178-5 [pii]
AID - 10.1016/j.expneurol.2019.113029 [doi]
PST - ppublish
SO  - Exp Neurol. 2019 Nov;321:113029. doi: 10.1016/j.expneurol.2019.113029. Epub 2019 
      Aug 1.