Learning and Memory issues in Down Syndrome

Researchers at the Centre for Genomic Regulation (CRG) discovered that the Snhg11 gene is essential for the function and development of neurons in the hippocampus. Experiments with rodents and human tissues found that the gene is less active in Down syndrome brains, which could explain the memory problems observed in people with the disorder. The findings were reported in the journal Molecular Psychiatry.

Historically, much of the focus in genomics has been on protein-coding genes, which account for only around 2% of the human genome. The rest is “dark matter,” which includes huge lengths of non-coding DNA sequences that do not create proteins but are increasingly understood to play roles in regulating gene activity, impacting genetic stability, and contributing to complex traits and disorders.

Snhg11 is a gene discovered in dark matter. It is a long, non-coding RNA that is transcribed from DNA but does not encode a protein. Non-coding RNAs have key roles in regulating normal biological processes, and aberrant expression has previously been connected to the development of human illnesses such as cancer. The study provides the first indication that a non-coding RNA plays an important role in the development of Down syndrome.

Down syndrome is a genetic disease caused by having an extra copy of chromosome 21, also known as trisomy 21. It is the most frequent hereditary cause of intellectual disability, affecting around five million people worldwide. People with Down syndrome experience memory and learning difficulties, which have previously been related to abnormalities in the hippocampus, a brain region important in learning and memory formation.

“The gene is especially active in the dentate gyrus, a section of the hippocampus that is essential for learning and memory and one of the few brain locations where new neurons are constantly formed throughout life. We discovered that abnormally expressed Snhg11 causes reduced neurogenesis and altered plasticity, which has a direct function in learning and memory, implying a crucial role in the pathophysiology of intellectual disability,” explains Dr. César Sierra, the paper’s first author.

The scientists investigated the hippocampus in mouse models with genetic characteristics similar to Down syndrome in people. The hippocampus has a variety of cell types, and the study sought to determine how the addition of an extra chromosome 21 influences these cells.

The researchers separated nuclei from brain cells and utilized single nucleus RNA sequencing to determine which genes were activated in each cell. One of the most startling findings came from dentate gyrus cells, where the researchers discovered a significant drop in Snhg11 expression. The researchers also discovered reduced levels of Snhg11 in the same sorts of tissues from human postmortem brains with trisomy 21, demonstrating its relevance to human instances.

To further understand the implications of lower Snhg11 expression on cognition and brain function, the researchers artificially reduced the gene’s activity in healthy mouse brains. They discovered that low levels of Snhg11 were sufficient to impair synaptic plasticity, the ability of neural synapses to increase or weaken over time. Synaptic plasticity is critical to learning and memory. It also inhibited the mouse’s ability to generate new neurons.

To further grasp the real-world implications of their findings, the researchers conducted a variety of behavior tests on mice. These investigations demonstrated that low levels of Snhg11 cause memory and learning impairments similar to those reported in Down syndrome, indicating that the gene regulates brain function.

Snhg11 has previously been associated with cell proliferation in various forms of cancer. The researchers intend to conduct additional research to determine the specific mechanisms of action involved, which could lead to new therapeutic strategies. They will also look into whether other genes containing long non-coding RNAs, many of which have yet to be found, could contribute to intellectual impairments.

“There are numerous therapies to assist people with Down syndrome in living independently, but only a few are pharmaceutical. Dr. Mara Dierssen, co-author of the paper and Group Leader of the Cellular & Systems Neurobiology lab at the Centre for Genomic Regulation, says that studies like this help lay the groundwork for finding strategies to improve memory, attention, and language functions, as well as to prevent cognitive decline associated with aging.

More information: The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity and memory deficits in Down syndrome, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02440-9

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