KCC2: unlocking the secrets of ‘over excited’ nerves

Combining rigorous neuroscience with drug discovery expertise is helping scientists in the IMED Biotech Unit at AstraZeneca to evaluate new targets, such as the neuronal potassium-chloride co-transporter protein KCC2, as potential future treatment opportunities in epilepsy and other neurological diseases.

In the latest publication in PNAS, our team of researchers at the AstraZeneca-Tufts Laboratory in Boston have provided more detailed analysis in mice of the essential role of KCC2 in controlling nerve excitation in the brain.

Down-regulation of KCC2 has been seen in a number of neurological diseases, and the protein is considered a key target in the search for new treatments for epilepsy.

“Epilepsy is today’s main interest but the ubiquitous role of KCC2 in nerve excitation in the brain means that it has potential as a target for innovative therapeutic interventions for other conditions, such as pain,” explains Dr Nick Brandon, Co-Director of the AstraZeneca-Tufts Neuroscience Laboratory and Chief Scientist in Neuroscience, IMED Biotech Unit.

This new research builds on the team’s previous findings published in Nature Medicine, where they built a battery of complex, cutting edge in vitro techniques to get ‘up close’ to what happens to chloride during nerve excitation. KCC2 and Gamma-Aminobutyric acid (GABA) type A receptors work as the neuronal ‘double act’ for controlling chloride transport in and out of cells – deficits of which can cause excessive nerve excitation in the brain and lead to seizures and other neurological abnormalities.

To validate the role of KCC2 in vivo, the team have genetically engineered a mouse model enhancing KCC2 activity and studying the impact on chemical-induced seizures. Modifying residues T906 and T1007 from threonines to alanines prevented the inactivating phosphorylation of KCC2, so enhancing its activity. The scientists were then able to demonstrate seizures were limited in mice with higher KCC2 activity levels. This work has the chance to guide therapeutic approaches for this target. 

 

 

“We are really excited by our latest publication on KCC2 – building on our previous work but now starting to get a feel for the therapeutic potential of the target. This paper provides the first evidence that increasing KCC2 activity is well tolerated (in mice), and may be an efficacious therapeutic strategy to treat epilepsy. This is another great example of the success of the Neuroscience drug discovery model we have implemented at Tufts in the AZ-Tufts lab.” Dr Stephen Moss, Professor of Neuroscience and Co-Director of the AstraZeneca-Tufts Neuroscience Laboratory.

The AstraZeneca-Tufts partnership, which recently celebrated its fifth anniversary, is proving a highly successful model for collaboration between academia and industry. This publication builds on previous papers in Scientific ReportsJournal of Biological Chemistry and Trends in Neuroscience in just the last year from the group together with IMED Biotech Unit scientists in this field, to understand the complexities of this mechanistic pathway in the brain. There are currently 12 AstraZeneca funded scientists working alongside researchers in the neuroscience department at Tufts, with a rapidly growing portfolio of high impact publications to their name.

“As I have stated before and still maintain – the lab is a true academic-industry hybrid . This paper in PNAS is a great example of the high-quality research being done in the lab, supporting our early discovery neuroscience portfolio but also developing the careers of the scientists who work with us” says Nick.

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