The triple dose of the GRIK1 gene, located on chromosome 21 and related to the balance of synaptic transmission in the brain, is one of the reasons why people with Down syndrome have a harder time orienting themselves spatially. Spanish researchers have proven in mice that, if the extra dose of this gene is normalized, spatial memory problems disappear.
The deficits in spatial memory in Down syndrome would be caused by minor modifications of synaptic transmission inhibiting the hippocampus, a structure of the brain associated with memory and spatial orientation.
Juan Lerma’s team, from the UMH-CSIC Institute of Neurosciences in Alicante, has identified the gene called GRIK1 –fundamental in the balance between excitation and inhibition in the brain– as one of the reasons why people with Down syndrome have problems of spatial orientation. The finding is published in the journal Nature Communications.
The GRIK1 gene is located on chromosome 21. People with Down syndrome have three copies of this gene instead of the usual two; therefore, they produce a higher dose of the protein it produces. This gene has a very important role in communication between neurons, regulating the release of the main inhibitory neurotransmitter in the brain, called GABA.
“We have seen in mouse models of Down syndrome that there is a problem of imbalance between excitation and inhibition of certain neuronal circuits of the hippocampus, a brain structure related to memory and orientation in space,” explains Lerma. “This imbalance depends on the dose of GRIK1. Through genetic manipulation techniques, we have normalized the dose of GRIK1 in our Down syndrome model, managing to reverse this imbalance between excitation and inhibition,” he adds.
In addition, it was observed that when normalizing the dose of this gene in the transgenic mice, spatial memory problems disappear, explains Sergio Valbuena, first author of the study.
To maintain proper brain function, a good regulation of communication between neurons is necessary. This communication is done through neurotransmitters and can be excitatory or inhibitory, equivalent to an ‘accelerator’ and a ‘brake’ of the nervous system. The release of excitatory or inhibitory neurotransmitters takes place at the points of contact between neurons, called synapses.
It is the correct balance of the excitatory and inhibitory neurotransmission that makes it possible for the neural circuits to function properly. When that balance is broken, different pathologies appear, including anxiety, depression, schizophrenia, bipolar or autistic spectrum disorder.
Professor Lerma points out that the changes that produce this imbalance between arousal and inhibition are subtle and had gone unnoticed throughout the years of study on Down syndrome.
Last year, this team already demonstrated how slight changes in the intensity of synaptic transmission cause significant changes in behavior, which manifest differently depending on the structure of the brain affected.
Down syndrome is the most frequent genetic cause of cognitive disability
When changes in the intensity of synaptic transmission take place in the brain tonsil, they affect emotional processing and can alter fear or anxiety responses. If they occur in the prefrontal cortex, they can lead to problems in personal relationships or an increase in aggressiveness, says Lerma.
And now this new study shows that a similar imbalance in the hippocampus results in alterations related to spatial memory, which are the cause of orientation problems suffered by people with Down syndrome.
Down syndrome is the most frequent genetic cause of cognitive disability, so unraveling the physiological mechanisms responsible for these deficits is an important challenge. Described for the first time in 1866 by John Langdon Down, to whom it owes its name, Down syndrome is characterized by the presence of an extra copy of chromosome 21 instead of the usual two, which gives rise to various medical problems.