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Exp Neurol. 2019 Nov;321:113029. doi: 10.1016/j.expneurol.2019.113029. Epub 2019 Aug 1.

Impact of mTOR hyperactive neurons on the morphology and physiology of adjacent neurons: Do PTEN KO cells make bad neighbors?

Author information

1
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.
2
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.
3
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.
4
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.

Abstract

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.

KEYWORDS:

Dentate gate; Dentate granule cell; Neurolucida; PTEN; Soma area; Somatic hypertrophy; mTOR

PMID:
31377403
PMCID:
PMC6744293
[Available on 2020-11-01]
DOI:
10.1016/j.expneurol.2019.113029

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