Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Abstract Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet. ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017

Experience-Induced Arc/Arg3.1 Primes CA1 Pyramidal Neurons for Metabotropic Glutamate Receptor-Dependent Long-Term Synaptic Depression

Summary A novel experience induces the Arc/Arg3.1 gene as well as plasticity of CA1 neural networks. To understand how these are linked, we briefly exposed GFP reporter mice of Arc transcription to a novel environment. Excitatory synaptic function of CA1 neurons with recent in vivo Arc induction (ArcGFP+) was similar to neighboring noninduced neurons. However, in response to group 1 metabotropic glutamate receptor (mGluR) activation, ArcGFP+ neurons preferentially displayed long-term synaptic depression (mGluR-LTD) and robust increases in dendritic Arc protein. mGluR-LTD in ArcGFP+ neurons required rapid protein synthesis and Arc, suggesting that dendritic translation of Arc underlies the priming of mGluR-LTD. In support of this idea, novelty exposure increased Arc messenger RNA in CA1 dendrites and promoted mGluR-induced translation of Arc in hippocampal synaptoneurosomes. Repeated experience suppressed synaptic transmission onto ArcGFP+ neurons and occluded mGluR-LTD ex vivo. mGluR-LTD priming in neurons with similar Arc activation history may contribute to encoding a novel environment

Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion

Human chromosome 16p11.2 microdeletion is the most common gene copy number variation in autism, but the synaptic pathophysiology caused by this mutation is largely unknown. Using a mouse with the same genetic deficiency, we found that metabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity and protein synthesis was altered in the hippocampus and that hippocampus-dependent memory was impaired. Notably, chronic treatment with a negative allosteric modulator of mGluR5 reversed the cognitive deficit