MedicalResearch.com Interview with:
Keerthi Krishnan PhD
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York 11724
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Rett Syndrome is diagnosed as a neurodevelopmental disorder in girls, caused mainly by mutations in the gene MECP2. Many previous studies, including mine, have shown that mutations in MECP2 result in improper communication between nerve cells in the brain during sensitive periods of development. However, it was unclear if the same mechanisms were responsible for cognitive and behavioral problems found in adulthood.
In this paper, we have utilized a natural, learned response called pup retrieval behavior to study adult neural plasticity in a female mouse model of Rett Syndrome. With some learning, adult female mice will gather scattered pups to the nest, in response to distress calls from the pups. We found that the Rett Syndrome model mice with reduced MECP2 protein do not gather pups efficiently. This is due to the abnormal formation of structures called perineuronal nets on a specific type of neurons (called parvalbumin+ GABAergic neurons) that block plasticity and prevent learning of the appropriate response. Furthermore, the same neural and molecular mechanisms found earlier in development were also found to mediate learning in adulthood.
MedicalResearch.com: What should readers take away from your report?
Response: There is a critical window of heightened sensitivity to cues from the senses – in this case, sounds made by newborn pups – during which neurons in adult females must be able to connect with others in order to learn a new behavior. Without appropriate Mecp2 function, such plasticity is inhibited leading to poor learning.
Learning associated with a range of other behaviors (e.g. motor, social, cognitive) might rely on similar molecular and neural circuit mechanisms. If we could understand these basic motifs, we might be able to elucidate the pathogenesis of the varied Rett Syndrome phenotypes.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: We were able to identify some key molecules that regulate plasticity in the previous studies. That could be the tip of the iceberg. Now, I am interested in systematically identifying other key molecules regulating neural plasticity in Rett Syndrome mouse models. This could have translational potential.
I am also interested in devising/utilizing other natural behaviors to target specific endophenotypes in Rett Syndrome in order to determine if the same motifs we found before are being disrupted.
MedicalResearch.com: Is there anything else you would like to add?
Response: Though most of the surviving patients of Rett Syndrome are female, there are very few basic research studies done in females to understand pathogenesis. A key feature of our paper is the use of female mouse models to determine Rett Syndrome pathogenesis.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice
Keerthi Krishnan, Billy Y. B. Lau , Gabrielle Ewall, Z. Josh Huang & Stephen D. Shea
Nature Communications 8, Article number: 14077 (2017)
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