Dietary beta-hydroxybutyrate is superior to a ketogenic diet to improve behavior and abnormal myelination in a mouse model of NMDA receptor deficiency

Background Dysfunction of N-methyl-D-aspartate receptors (NMDAR) is associated with idiopathic autism and a syndromic form of autism called GRIN disorder. Ketogenic therapy is used to treat seizures in GRIN disorder, but it is unknown whether it improves other aspects of the disorder. We asked whether a ketogenic diet or exogenous ketone bodies, beta-hydroxybutyrate (BHB), could improve autism-like behaviours in Grin1 knockdown mice (Grin1KD). Since BHB has been reported to affect myelination, we asked whether improvements in behavior were correlated with changes in myelination. Methods WT and Grin1KD mice were randomly assigned to receive control, ketogenic diet (6:1 fat to proteins and carbohydrates ratio), or normal chow with BHB supplementation (6mg/ml in drinking water) starting at postnatal week 3-4. Blood ketones were monitored one-week and nine-week after treatment. Following this, behavioural tests were conducted, and subsequently the myelin integrity of the corpus callosum was studied with transmission electron microscopy. Results Ketogenic diet was not well-tolerated by juvenile Grin1KD mice in contrast to BHB supplementation. Both dietary manipulations elevated blood ketone levels after one week of treatment, but these elevations diminished over time. Both treatments reduced hyperactivity of Grin1KD mice. However, only BHB improved sensorimotor gating in Grin1KD mice. Social motivation and spatial working memory were not improved by either treatment. We report, for the first time, a reduced percentage of myelinated axons in the corpus callosum of adult Grin1KD mice, which was ameliorated by long-term BHB supplementation. Surprisingly, mice receiving a ketogenic diet showed increased number of abnormal myelinations, especially decompaction. Limitations Our findings are limited to the specific ketogenic regimens. Although findings in Grin1KD mice have significant implications in ASD and GRIN disorder, mice and humans have fundamental differences in their dietary and metabolic requirements. Future studies are required to understand the mechanism by which ketone bodies improve myelination. Conclusions We demonstrate that sub-chronic administration of exogenous BHB from early-life is beneficial to some domains of ASD-linked behaviours in Grin1KD mice. One potential mechanism is by improving myelination in the corpus callosum of Grin1KD mice. Our data supports exogenous BHB supplementation as potential treatment for ASD and GRIN disorder.