Researchers may have found the cause underlying the learning and memory impairments that characterize Down's syndrome. A protein called sorting nexin 27 (SNX27) in the brain is depleted in the brains of people with Down's syndrome, and restoring the protein in mice that model the disorder rescues the cognitive deficits (Nat. Med. published online 24 March 2013; doi:10.1038/nm.3117).

A team of researchers led by Huaxi Xu (Sanford-Burnham Medical Research Institute, La Jolla, CA) began by studying mice that are genetically deficient in SNX27 and noticed that they had several deficits characteristic of Down's syndrome patients, including fewer neurons in the hippocampus and cortex, defective synaptic functioning, and learning and memory impairments. The neurons of the mice also had reduced amounts of glutamate receptors, which are crucial for proper functioning of the neurons that underlie learning and memory. SNX27 helps keep glutamate receptors on the cell surface in neurons, and so without proper levels of SNX27, the neurons cannot function properly.

The researchers supposed that a SNX27 deficiency could be to blame in humans with Down's syndrome as well. They looked at levels of SNX27 in brains of humans with the condition and confirmed that there were significantly lower than normal levels of SNX27. There was also reduced expression of a protein called C/EBPβ, which is necessary for SNX27 to be properly expressed. They discovered that C/EBPβ is negatively regulated by a microRNA called miR-155. This microRNA is encoded on chromosome 21; Down's syndrome patients have an extra copy of this chromosome, so they have increased levels of miR-155. In turn, the increased miR-155 leads to a decrease in C/EBPβ expression, which then reduces SNX27 expression, impairing localization of glutamate receptors in hippocampal and cortical neurons and resulting in cognitive deficits.

The team hopes to use this discovery to develop novel treatments for those living with Down's syndrome. They delivered human SNX27 into the brains of the Down's syndrome–modeling mice using a noninfectious virus delivery method. The increased levels of SNX27 in the hippocampus of the mice rescued their synaptic and cognitive deficits. Unfortunately, the same delivery system cannot safely be used in humans, so finding a treatment approach with SNX27 will not be quite so simple. The scientists are currently screening for small molecules that could be used as a drug to increase SNX27 levels.