Vitamin D Eases Behavior Problems in Rett Mouse Model
Supplementing with Vitamin D rescued the altered activity of genes associated with Rett syndrome and improved behaviors in a mouse model, a study showed.
The findings indicate that supplementation could provide a simple, cost-effective therapeutic option to help Rett patients, the scientists said.
About 95% of Rett syndrome cases are caused by defects in MECP2, a protein that regulates the activity of other genes and plays a critical role in brain development and function.
Because of its role in gene activation, a lack of MECP2 leads to disruptions in many cellular pathways, including the abnormal activation of the NF-kappaB pathway, which regulates cell growth and survival, as well as immune responses and inflammation.
Studies show that blocking the NF-kappaB pathway in Rett mouse models eases hallmark symptoms, suggesting that suppressing NF-kappaB may be a potential treatment strategy for Rett patients.
Vitamin D is known to block the NF-kappaB pathway, reduce NF-kappaB protein levels, and decrease the levels of pro-inflammatory immune signaling molecules. Levels of the vitamin are low in both Rett mouse models and patients.
Vitamin D also regulates other signaling pathways disrupted in Rett, suggesting that taking supplements may decrease symptoms by modulating multiple disease-related pathways.
Scientists at Syracuse University in New York investigated its impact on the expression (activity) of genes altered in the brain of a Rett mouse model, and on their behavior.
Female Rett mice and their healthy litter mates were placed on control — 1 international units (IU)/g vitamin D — or supplemented (10 IU/g vitamin D) chow at the age of 4 weeks, before the onset of overt behavioral symptoms. Supplementation nearly doubled the vitamin’s levels in the bloodstream by 5 months of age.
Experiments confirmed that supplementing modified gene activity in the brains of healthy mice, with more than 3,000 genes expressing differently with supplementation than without. Among these, 1,350 genes have a sequence indicating they “could be directly regulated by vitamin D,” the team wrote.
Further, vitamin D treatment normalized the expression of multiple genes altered in the brains of Rett mice, and this change rescued defects in nerve cell structure.
The team then investigated whether these changes in gene expression with supplementation correlated with behavioral changes in Rett mice and control litter mates.
At 5 months of age, Rett mice on the supplemented diet showed significant motor coordination improvements on a rotarod test compared to Rett mice on the control diet, but not to the levels of healthy mice. By 7 months, these improvements were not sustained. The rotarod performance test measures the balance or endurance of a rodent based on how long it can remain on a mechanically turning horizontal cylinder.
“This suggests that dietary vitamin D supplementation partially delays the decline in motor coordination but does not fully prevent or rescue it,” the researchers wrote.
Supplementing did not reduce anxiety-like behavior in an open-field test in early and mid-symptomatic stages. Still, by 7 months, Rett mice on the supplemented diet did not show increased anxiety when compared to healthy mice, “suggesting an improvement in anxiety-like behavior with vitamin D supplementation,” they added.
Additional control experiments showed that a diet deficient in vitamin D did not worsen these behavioral characteristics.
The researchers then examined whether behaviors correlated with vitamin D levels circulating in the bloodstream measured at 7 months. Specifically, levels of the precursor 25(OH)D (calcidiol) were measured because they best correlate with the levels of the active form of vitamin D, called 1,25(OH)D (calcitriol), in the brain.
As expected, a diet deficient in vitamin D led to a significant drop in 25(OH)D levels in both Rett and healthy mice. The supplemented diet, by contrast, increased 25(OH)D, but not to statistically significant levels.
Rett mice with insufficient 25(OH)D traveled significantly less in the open-field test than healthy mice in any group and showed increased anxiety-like behavior. Rett mice with sufficient 25(OH)D concentrations did not show increased anxiety in the test.
“Thus, our results suggest that low levels of serum 25(OH)D in [Rett] mice could contribute to exploratory motor and anxiety-like behavioral deficits,” the scientists wrote.
Vitamin D in the blood is converted to 25(OH)D in the liver, then 1,25(OH)D is transported to the kidneys where it is processed into calcitriol. In Rett mice, the expression of genes involved in vitamin D metabolism was altered in both the liver and kidney, but not in the brain, indicating that the alterations in its metabolism might be specific to tissues outside the brain, the team noted.
“Treating RTT [Rett] will likely require a combinatorial approach, restoring [metabolism] to multiple disrupted cellular pathways that additively contribute to RTT [characteristics],” the investigators wrote. “Vitamin D has the ability to modify multiple of these disrupted cellular pathways in parallel.”
Vitamin D “has the potential to provide valuable benefit to the quality of life of RTT patients,” they added.