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

Research output: Contribution to journalArticle

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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
Externally publishedYes

Fingerprint

Ketogenic Diet
Seizures
Phenotype
Brain
Glucose
Cerebrospinal Fluid
Adenosine Triphosphate
Insulin
Hydroxybutyrates
Metabolome
Facilitative Glucose Transport Proteins
Autistic Disorder
Ketones
Hypoglycemia
Amyloid
Ultrasonics
Electroencephalography
Lactic Acid
Proteins

ASJC Scopus subject areas

  • Endocrinology

Cite this

Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice : Ketogenic diet ameliorates electroencephalographic seizures and improves sociability. / Dai, Yun; Zhao, Yuanzi; Tomi, Masatoshi; Shin, Bo Chul; Thamotharan, Shanthie; Mazarati, Andrey; Sankar, Raman; Wang, Elizabeth A.; Cepeda, Carlos; Levine, Michael S.; Zhang, Jingjing; Frew, Andrew; Alger, Jeffry R.; Clark, Peter M.; Sondhi, Monica; Kositamongkol, Sudatip; Leibovitch, Leah; Devaskar, Sherin U.

In: Endocrinology, Vol. 158, No. 4, 01.04.2017, p. 936-949.

Research output: Contribution to journalArticle

Dai, Y, Zhao, Y, Tomi, M, Shin, BC, Thamotharan, S, Mazarati, A, Sankar, R, Wang, EA, Cepeda, C, Levine, MS, Zhang, J, Frew, A, Alger, JR, Clark, PM, Sondhi, M, Kositamongkol, S, Leibovitch, L & Devaskar, SU 2017, 'Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice: Ketogenic diet ameliorates electroencephalographic seizures and improves sociability', Endocrinology, vol. 158, no. 4, pp. 936-949. https://doi.org/10.1210/en.2016-1816
Dai, Yun ; Zhao, Yuanzi ; Tomi, Masatoshi ; Shin, Bo Chul ; Thamotharan, Shanthie ; Mazarati, Andrey ; Sankar, Raman ; Wang, Elizabeth A. ; Cepeda, Carlos ; Levine, Michael S. ; Zhang, Jingjing ; Frew, Andrew ; Alger, Jeffry R. ; Clark, Peter M. ; Sondhi, Monica ; Kositamongkol, Sudatip ; Leibovitch, Leah ; Devaskar, Sherin U. / Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice : Ketogenic diet ameliorates electroencephalographic seizures and improves sociability. In: Endocrinology. 2017 ; Vol. 158, No. 4. pp. 936-949.
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AU - Shin, Bo Chul

AU - Thamotharan, Shanthie

AU - Mazarati, Andrey

AU - Sankar, Raman

AU - Wang, Elizabeth A.

AU - Cepeda, Carlos

AU - Levine, Michael S.

AU - Zhang, Jingjing

AU - Frew, Andrew

AU - Alger, Jeffry R.

AU - Clark, Peter M.

AU - Sondhi, Monica

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AU - Devaskar, Sherin U.

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