Worldwide, one in about 1,000 newborns is diagnosed with Down syndrome, a genetic disorder predominantly caused by an extra copy of chromosome 21—also known as trisomy 21—and in countries such as the US the number of children affected by the condition appears to be increasing. No medicines can currently treat the memory and learning impairments seen in Down syndrome; a new study published today in the Journal of Clinical Investigation could offer insight into the cellular pathways to target to improve cognitive function.

In the study, Italian researchers report that a one-month lithium treatment promotes the growth of new neurons in the hippocampus and improves cognitive functions in an animal model of Down syndrome. The team, led by neuroscientist Laura Gasparini at the Italian Institute of Technology in Genoa, took advantage of the fact that mice with an extra copy of chromosome 16 demonstrate cognitive impairment and neuronal dysfunction similar to that seen in trisomy 21. “We hypothesized that stimulating the growth of new neurons in this mouse model will benefit cognitive function in Down syndrome,” Gasparini says.

The scientists gave the genetically engineered mice lithium—a drug already used to treat mood disorders in people. Previous studies, including one in 2010 in these mice, have shown that lithium increases the production of new brain cells in a region know as the hippocampus, which has a key role in memory. In their experiment, Gasparini and her colleagues measured the expression of a marker, doublecortin (DCX), which is present on the surface of newly formed neurons.

At the end of the one month treatment, the ‘Down syndrome’ mice who received lithium had approximately 3,500 cells in the hippocampus expressing DCX, about the same number as that seen in healthy mice without the condition. By comparison, those mice with the trisomy mutation that received saline solution only had about 1,500 cells expressing DCX, indicating that they had about 40% fewer newly formed neurons. Additionally, trisomic mice that received lithium treatment performed much better than their untreated counterparts on the behavioral assessments designed to test their contextual learning by fear conditioning, spatial memory and object discrimination.

Notably, this new study claims to identify a molecular mechanism by which lithium increases the formation of new neurons in the hippocampus—at least in mice: Administering the drug in the rodents activated what’s known as the beta-catenin/Wnt signaling pathway, that earlier research has implicated in neuronal development. Treating trisomic mice with lithium resulted in 50% increase in the activation of this signaling pathway compared with untreated mice.

Looking ahead

“Our data encourages exploration of lithium-based therapies in human patients as means of repairing the cognitive defects of Down syndrome,” Gasparini says.

This new work provides “an important framework for therapeutic strategies to improve brain alternation in Down syndrome,” says Renata Bartesaghi, a neurologist at the University of Bologna in Italy who led the 2010 study. “It would be worthwhile to establish if lithium improves cognitive function in human Down syndrome patients.”

A clinical trial that tested lithium in individuals with Down syndrome was recently completed at King’s College London, but the principal investigator, Declan Murphy, says it’s too early to know what effect the intervention had. Murphy acknowledged, however, that lithium therapy requires close monitoring due to possible negative effects on white blood cells as well as the thyroid and heart, just to name a few. “This is a particular potential area of difficulty in people with Down syndrome as they frequently already have compromised thyroid and cardiac function,” Murphy says.

Neurologist Alberto Costa, of the University of Colorado-Denver School of Medicine, adds that even though lithium is currently prescribed for bipolar disorders, its prolonged use has been linked to kidney damage. “We need to be very careful when translating these findings into clinical application,” he says. Nonetheless, Costa says that lithium can initially be used to identify important pathways and mechanisms that improve cognition in human Down syndrome patients, enabling screenings for most effective and least toxic cognitive-boosting compounds.

Murphy is equally convinced that the field will make progress: “The key will be to identify treatments that are able to target new mechanisms for reducing disease burden.”

Meanwhile, Costa is involved in a Down syndrome clinical trial testing the effect of memantine, a drug approved in October 2003 by US Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease and sold under the name Namenda by Forest Laboratories. The trial, which launched in 2010, is still ongoing.

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