Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
A weakened recurrent circuit in the hippocampus of Rett syndrome mice disrupts long-term memory representations
We previously published about this research in a story titled “Study: Improving Memory Recall in Rett Syndrome” which can be found here. This study was first published in the scientific journal Neuron. You can view the abstract of the study here.
This research team was affiliated with the Baylor College of Medicine and the Jan and Dan Duncan Research Institute at Texas Children’s Hospital.
What Happened?
Rett syndrome is a rare genetic disorder that impacts girls. As a progressive disease, cognitive abilities of these patients tend to decline with age, including dementia and difficulties with long-term memory. In this study, a mouse model of the disorder displays impairment of long-term contextual memory recall. The research team set out to determine if there was a method that could help reduce the loss of long-term memory seen in the model.
Contextual memories are those in which an event is encoded along with the circumstances surrounding the experience. Previous studies have suggested that the loss of these memories is the result of disruptions which affect the balance of inhibitory and excitatory synaptic signals that act on the hippocampal neurons. The team hypothesized that this disruption altered the composition and size of the hippocampal neurons, which are critical for the encoding of these memories.
The scientists used a very small microscope to monitor this ensemble as the Rett syndrome mice attempted to recollect a frightening experience. They also did the same with regular mice and found that the diseased mice had more correlated ensembles that were of greater size. This suggests that the pyramidal neurons of the hippocampus were not being inhibited enough in these mice. The researchers then sought to find out which neuron was failing to provide the inhibiting effect.
They used slices of brain and recorded neuronal activity in each one. In the Rett syndrome mice, connectivity between the pyramidal neurons and OLM cells, which are a subset of inhibitory neurons which express somatostatin, was substantially reduced. They then used a chemical-genetic technique in order to enhance the activation of the OLM cells and found that memory recall was restored after doing so.
About Rett Syndrome
Rett syndrome is a brain disorder that becomes evident early in the lives of its female patients. The disease is caused by a genetic mutation that affects the MECP2 gene. This gene is found on the X chromosome. Boys who have this mutation typically die soon after being born, so Rett syndrome almost exclusively affects girls. It occurs as a spontaneous mutation in the vast majority of cases, and is rarely inherited from parents. Symptoms include sleeping issues, difficulty speaking, poor coordination, scoliosis, seizures, small head size, slow growth, and repetitive movements. There is no cure for Rett syndrome, and management focuses on maintaining function and alleviating symptoms. Life expectancy for patients is around 40 years. Death often occurs spontaneously, and is often linked to brainstem malfunction, gastric perforation, or cardiac arrest. To learn more about Rett syndrome, click here.
Why Does it Matter?
The findings from this research constitute a major revelation in the mechanism behind one of Rett syndrome’s most devastating symptoms. With the discovery of this mechanism, future research could potentially work towards a treatment that could help treat or slow the decline of memory in people living with this disorder:
“This is the first study to demonstrate that upregulating the activity of SOM neurons can improve memory recall and retrieval capacity in Rett mice…It opens exciting areas of research to explore therapeutic possibilities that could improve contextual memory recall in individuals affected by Rett syndrome. These findings have a much broader implication and are also applicable to other neurological disorders in which the development and function of inhibitory circuits are altered.” – Dr. Huda Zoghbi, distinguished service professor, Baylor College of Medicine, and director, Jan and Dan Duncan Neurological Research Institute
Rett syndrome is a devastating genetic disorder with no cure or treatments that can truly halt or slow the progression of the illness. Research breakthroughs such as this are critical to developing treatments like gene therapy that can transform outcomes for patients. While it may be years before this data translates into a treatment, it nevertheless offers hope for future generations affected by the disorder.
