Ketogenic diet improves motor and anxiety-like behaviors plus cerebellar inflammation via axonal remyelination in the BTBR mouse model of autism.

Different evidence suggests that ketogenic diet (KD) ameliorates neurological dysfunctions including core symptoms of autism spectrum disorders (ASD). In view of this, we have hypothesized that KD may induce a positive effect even on some ASD comorbidities, such as motor impairment and anxiety, along with cerebellar inflammation and axonal demyelination. BTBR T+ Itpr3tf/J (BTBR) and C57BL/6 (C57) mice were fed with a standard chow diet (CD) or KD for 5 weeks. Modified beam walking (MBW) and open field (OFT) tests were used to examine locomotor activity and anxiety-related behaviors. At the same time, cerebellar pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were evaluated together with g-ratio of myelinated axons, detected by TEM. The levels of different isoforms (21.5, 18.5/17, and 14-kDa) of the myelin basic protein (MBP) were also analyzed. As expected, KD improved motor deficits and anxiety in BTBR mice as displayed by significant increases (P<.001) in the number of peeking and laps during MBW test rather than BTBR treated with CD. Furthermore, reduced path speed and enhanced path length (P<.001) in OFT were reported for the same KD-fed mice strain. Contextually, some pro-inflammatory cytokines (TNF-α and IL-1β) were significantly (P<.05) reduced in the cerebellum of BTBRs exposed to KD. Such ameliorations were correlated to a reduction of g-ratio (P<.001), together with an upregulation (P<.05) of the MBP isoform 18.5/17-kDa. Overall, these findings support a promyelinating and anti-inflammatory action of KD, which very likely determined mitigation of motor disorder and anxiety-like behaviors.