Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability.
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.
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.
Yun
Y
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
Y
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
M
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
BC
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
S
Thamotharan
Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Andrey
A
Mazarati
Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Raman
R
Sankar
Intellectual and Developmental Disabilities Research Center and Brain Research Institute, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Elizabeth A
EA
Wang
Intellectual and Developmental Disabilities Research Center and Brain Research Institute, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Carlos
C
Cepeda
Intellectual and Developmental Disabilities Research Center and Brain Research Institute, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Michael S
MS
Levine
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Intellectual and Developmental Disabilities Research Center and Brain Research Institute, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Jingjing
J
Zhang
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Ahmanson-Lovelace Brain Mapping Center,  Department of Neurology, UCLA, Los Angeles, California, USA.
Andrew
A
Frew
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Ahmanson-Lovelace Brain Mapping Center,  Department of Neurology, UCLA, Los Angeles, California, USA.
Jeffry R
JR
Alger
Department of Molecular and Medical Pharmacology and Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Peter M
PM
Clark
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.
Monica
M
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
S
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
L
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
SU
Devaskar
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D055423:Diet, Ketogenic; D004569:Electroencephalography; D005260:Female; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000178:diet therapy* / Q000378:metabolism / Q000503:physiopathology; D012737:Sex Factors; D012919:Social Behavior; D065853:Spatial Learning / Q000502:physiology; D014828:Vocalization, Animal / Q000502:physiology
D015816:Cell Adhesion Molecules, Neuronal; D051274:Glucose Transporter Type 3; D009419:Nerve Tissue Proteins; C527118:Nlgn4 protein, mouse; D005947:Glucose