Researchers at Stanford University School of Medicine and the University of California have now suggested a possible treatment for the neurological manifestations of Down’s syndrome. The team carried out experiments in a well established mouse model of Down’s syndrome. The mice, which have three copies of a fragment of mouse chromosome 16, show abnormal responses in behavioural tests of contextual learning such as conditioned fear learning. The mice also did not build nests when placed in a strange environment, unlike wild type animals. When the team examined the mice, they found significant neurodegeneration in the locus coeruleus region of the brain – an area that also degenerates in the brains of people with Down’s syndrome. The locus coeruleus supplies the hippocampus with the neurotransmitter, norepinephrine (noradrenaline), and when the genetically engineered mice were treated with L-DOPS (L-threo-dihydroxyphenylserine), a prodrug of norepinephrine and epinephrine which can cross the blood-brain barrier, they behaved much more like normal animals in both fear conditioning tests and nest building activities. Direct examination of neurons in the hippocampus of the genetically altered mice showed that these cells responded well to norepinephrine.
Degeneration in the locus coeruleus also occurs in other dementias, including Alzheimer’s disease, and mice with three copies of the gene expressing APP had fewer neurons producing norepinephrine than those with just two copies.
The authors hope that early intervention with agents targeting the norepinephrine system could lead to improvements in cognitive function in children with Down’s syndrome. Since improvements were seen even in the presence of established neurodegeneration in the genetically engineered mice, such agents may also have a role in restoring function in older individuals with Down’s syndrome and in Alzheimer’s disease sufferers. Previous studies of drug treatments for Down’s syndrome have focused on the neurotransmitter acetylcholine, which also acts at the hippocampus. Based on the new findings, the researchers suggest that the ideal treatment approach for improving cognition in people with Down’s syndrome will likely enhance both norepinephrine and acetylcholine signalling.
The study is published in Science Translational Medicine.