Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability

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.

Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?

“…It is becoming apparent that beneficial effects of ketogenic therapy extend beyond epilepsy, neurodegenerative disorders, and brain/spinal cord injury. The KD is broadly effective in improving core behavioral symptoms in animal models of autism spectrum disorder (Ruskin et al, 2013b , 2017a , b ; Ahn et al, 2014 ; Verpeut et al, 2016 ; Castro et al, 2017 ; Dai et al, 2017 ), and in autistic patients (Evangeliou et al, 2003 ; Masino et al, 2011b ; Spilioti et al, 2013 ). The KD is receiving growing interest in oncology as tumors are highly glucose-dependent (the Warburg effect; Seyfried and Mukherjee, 2005 ; Zuccoli et al, 2010 ; Schmidt et al, 2011 ; Klement et al, 2016 ; Lussier et al, 2016 ; Khodadadi et al, 2017 ).…”

Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures

“…Teasing out male mice from female ones, albeit underpowered, revealed IUGR male mice to be more vulnerable than female mice. These results suggest that perhaps unlike the case of GLUT3 in adult brain [59], here, E19 IUGR male and female animals when separated showed similar changes in brain GLUT3. However, in IUGR brain serotonin-SERT, the possibility exists that the male mice are more vulnerable than female ones.…”

“…These changes may have their roots in altered embryonic development of neural cellular processes [51], which may have resulted or in turn have affected the neuronal glucose transport mediated by GLUT3. While it is difficult to quantify the neuronal glucose transport function in vivo, separate from the blood-brain barrier and glial GLUT1 [6, 7, 59], one can surmise from in vitro experiments that a reduction in neuronal GLUT3, which activates adenosine monophosphate protein kinase, leads to diminution of ATP interfering with neurotransmission [12].…”

The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology

“…However, GLUTs are widely expressed with GLUT1 at the blood-brain barrier and GLUT3 important for neurons, complicating treatment options for brain tumors. Nevertheless, there is hope that in combining GLUT inhibitors and the ketogenic diet, another way to decrease glucose availability to the tumor while providing ketones for an alternative fuel, could ameliorate potential side effects (150)(151)(152). While the ketogenic diet was originally developed to treat epilepsy, it has been of interest for cancer therapy (152)(153)(154)(155)(156)(157)(158), with multiple trials currently listed on clinicaltrials.gov as recruiting patients.…”