Journal article
Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability
Endocrinology (Philadelphia), v 158(4), pp 936-949
01 Apr 2017
PMID: 28324109
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.
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Details
- Title
- Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability
- Creators
- Yun Dai - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Yuanzi Zhao - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Masatoshi Tomi - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Bo-Chul Shin - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Shanthie Thamotharan - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Andrey Mazarati - University of California, Los AngelesRaman Sankar - David Geffen School of Medicine at UCLAElizabeth A Wang - Semel Institute for Neuroscience and Human BehaviorCarlos Cepeda - Semel Institute for Neuroscience and Human BehaviorMichael S Levine - Semel Institute for Neuroscience and Human BehaviorJingjing Zhang - Department of NeurologyAndrew Frew - Department of NeurologyJeffry R Alger - Department of NeurologyPeter M Clark - David Geffen School of Medicine at UCLAMonica Sondhi - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Sudatip Kositamongkol - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Leah Leibovitch - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.Sherin U Devaskar - Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.
- Publication Details
- Endocrinology (Philadelphia), v 158(4), pp 936-949
- Grant note
- U54 HD087101 / NICHD NIH HHS R01 HD081206 / NICHD NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000398718200023
- Scopus ID
- 2-s2.0-85016775423
- Other Identifier
- 991019356344904721
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- Web of Science research areas
- Endocrinology & Metabolism