Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability
| Autor: | Andrew Frew, Shanthie Thamotharan, Jingjing Zhang, Bo-Chul Shin, Carlos Cepeda, Jeffry R. Alger, Yun Dai, Sudatip Kositamongkol, Michael S. Levine, Yuanzi Zhao, Monica Sondhi, Raman Sankar, Andrey Mazarati, Sherin U. Devaskar, Peter M. Clark, Masatoshi Tomi, Elizabeth A. Wang, Leah Leibovitch |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty CSF glucose Cell Adhesion Molecules Neuronal medicine.medical_treatment Glucose uptake Spatial Learning Nerve Tissue Proteins Hypoglycemia Mice 03 medical and health sciences Sex Factors 0302 clinical medicine Endocrinology Memory Seizures Internal medicine medicine Animals Social Behavior Research Articles Mice Knockout Behavior Animal Glucose Transporter Type 3 biology business.industry Insulin Glucose transporter Brain Electroencephalography medicine.disease Glucose 030104 developmental biology biology.protein Female GLUT1 Vocalization Animal Diet Ketogenic business 030217 neurology & neurosurgery GLUT3 Ketogenic diet |
| Zdroj: | Endocrinology. 158:936-949 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2016-1816 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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