Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice: Ketogenic diet ameliorates electroencephalographic seizures and improves sociability

Yun Dai, Yuanzi Zhao, Masatoshi Tomi, Bo Chul Shin, Shanthie Thamotharan, Andrey Mazarati, Raman Sankar, Elizabeth A. Wang, Carlos Cepeda, Michael S. Levine, Jingjing Zhang, Andrew Frew, Jeffry R. Alger, Peter M. Clark, Monica Sondhi, Sudatip Kositamongkol, Leah Leibovitch, Sherin U. Devaskar

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8 Citations (Scopus)

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 femalemice (5months 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 8months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learningandmemory, andreducedseizure events.We concludethat (1) sexspecific 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.

Original languageEnglish
Pages (from-to)936-949
Number of pages14
JournalEndocrinology
Volume158
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1

ASJC Scopus subject areas

  • Endocrinology

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    Dai, Y., Zhao, Y., Tomi, M., Shin, B. C., Thamotharan, S., Mazarati, A., Sankar, R., Wang, E. A., Cepeda, C., Levine, M. S., Zhang, J., Frew, A., Alger, J. R., Clark, P. M., Sondhi, M., Kositamongkol, S., Leibovitch, L., & Devaskar, S. U. (2017). Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice: Ketogenic diet ameliorates electroencephalographic seizures and improves sociability. Endocrinology, 158(4), 936-949. https://doi.org/10.1210/en.2016-1816