Objectives: 1. To evaluate age-dependent trends in MS mRNA status in postmortem samples of human cortex. 2. To evaluate MS mRNA status in cortex of autistic subjects vs. age-matched controls.
Methods: Standard PCR and qRT-PCR were carried out using primers targeted to cobalamin-binding and cap domains of MS. Amplified MS transcript levels were normalized to GAPDH levels.
Results: In control subjects the MS mRNA level displayed a dramatic age-dependent decrease across the lifespan, amounting to a more than 1000-fold reduction from 28 weeks of fetal gestation to 84 yrs of age. From fetal to 18 yrs the decrease in mRNA was rapid, while a slower decrease prevailed thereafter. In autistic subjects (4-30 yrs of age), MS mRNA levels were significantly reduced, and the decrease was greatest for the youngest individuals. The normally present initial phase of decrease was absent, due to the premature occurence of low levels. This pattern is consistent with an adpative response to oxidative stress which can accompany neuroinflammation.
Conclusions: Our studies demonstrate that the level of MS mRNA in the brain is high during fetal development and gradually decreases with age. This decrease is likely to be important for the normal progression of development, via its influence over DNA and histone methylation. MS mRNA levels in the cortex are abnormally low in autism, which is likely to reflect the presence of oxidative stress. Therapies which counteract oxidative stress and promote methylation may be a useful strategy in treating autism.