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Researchers at University College London (UCL) have identified specific regions of chromosome 21 that cause memory and decision-making problems in mouse models of Down syndrome (DS). The findings provide valuable new insights into the potential genetic mechanisms that underpin cognitive deficiencies associated with DS in humans, and could also help researchers to develop new therapeutic strategies.

“We have shown—for the first time—that different and multiple genes are contributing to the various cognitive problems associated with Down syndrome,” commented Matthew Walker, PhD, professor of neurology, at UCL Queen Square Institute of Neurology, who is co-author of the team’s published paper in Cell Reports. Walker and colleagues at UCL, Cardiff University, and the Francis Crick Institute, described their findings in a paper titled, “Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome.”

Normal human body cells contain 23 pairs of chromosomes—giving a total of 46 chromosomes in each cell. DS is a complex cognitive disorder that is caused when cells carry an extra copy of chromosome 21 (Hsa21), which carries more than 200 genes. Down syndrome is characterized by intellectual disability and significant problems in planning, decision-making, and memory function, which are thought to be caused by functional abnormalities in the hippocampus and medial prefrontal cortex (mPFC) regions of the brain.

The incidence of Down syndrome is currently about 1 in 800 live births worldwide, but is also on the rise, the authors wrote. “The current global population of people with DS is estimated at six million, and prevalence is rising, primarily due to an increase in maternal age (a major risk factor for DS) and increased life expectancy in people with DS resulting from reduced infant mortality rates and improved access to healthcare.”

Chromosome 21 and its genes are also found in mice, but in mice, the genes found on the single human chromosome have dispersed, in gene clusters, onto smaller regions on three different mouse chromosomes. These are mouse chromosomes 16, 10, and 17, which contain 148 genes, 62 genes, and 19 genes, respectively. In their reported study, Walker and colleagues studied three different strains of mouse that each contained an extra copy of the gene clusters on mouse chromosome 16, 10, or 17, which matched those on human chromosome 21. Their aim was to try and find out how the extra chromosome 21 genes in humans with Down syndrome might cause learning and memory disabilities.

“To further elucidate the neural mechanisms underlying cognitive deficits associated with DS, we studied three chromosome-engineered mouse models that each exhibit trisomy for one region of orthology with human chromosome Hsa21: the Dp1Tyb, Dp10Yey, and Dp17Yey strains … In combination, these three mouse strains are triplicated for almost all the genes on Has21,” the investigators wrote. The team reasoned that the three different mouse strains might show distinct features of cognitive disability, that were associated with distinct changes in brain activity in the hippocampus and mPFC.

To test their hypothesis the investigators subjected the mice to navigation tests, which required the animals to negotiate a simple “left-right” T-maze. Each group was measured for both memory and decision-making ability. During the tests, electrical activity in the hippocampus and mPFC was also monitored using an electroencephalogram (EEG).

The results showed that, compared with control animals, the Dp10Yey mouse strain had worse memory, and exhibited irregular brain circuitry in the hippocampus, which is a brain region known to be important for memory. The Dp1Tyb mice had worse decision-making ability and demonstrated poor brain signaling between the hippocampus and the PFC, which is needed for planning and decision-making. The third, Dp17Yey mice had no unusual electrical activity in the brain.

“The present study reveals distinct cognitive deficits and electrophysiological differences in three mouse models of DS, which, combined, carry duplications covering all Hsa21-orthologous regions,” the authors concluded. “These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21 … Importantly, our results imply that specific cognitive deficits in DS may result from different underlying genetic, functional, and regional abnormalities. This has important implications for understanding such cognitive deficits and indicates that therapies in DS will likely need to target multiple processes.”

Walker commented, “These findings are a complete surprise—we did not expect the three different gene groups would act completely differently. Scientists have traditionally worked on the hypothesis that a single gene, or single genes, was the likely cause of intellectual disabilities associated with Down syndrome.” Corresponding author Elizabeth Fisher, PhD, professor of neurogenetics at UCL Queen Square Institute of Neurology, noted, “Our study provides critical insights into the mechanisms underlying neuro-disability in Down syndrome and indicates that intellectual disability in Down syndrome may result from different underlying genetic, functional, and regional brain abnormalities. This implies that therapies for people with Down syndrome should perhaps target multiple processes, and we have made the initial steps in identifying what some of these processes are.”

The researchers will continue their research to discover specifically which gene or genes within the smaller gene groups are responsible for the observed impaired memory and decision-making problems observed in their mouse models.

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