Sön 26 maj / År 42 / Nr 1 2024

Newly discovered molecule in the brain’s signaling system to be developed into a novel drug target

To increase our knowledge about how the brain works and awareness of our behavior and mental health, we need to understand the interactions between different parts of the nervous system. With access to new technologies and advanced genetic analysis, researchers at Uppsala University have succeeded in identifying a new drug target.

Professor Klas Kullander leads a well-established team of researchers at the Department of Neuroscience. The team recently made a breakthrough discovery with regards to the brain’s communication system, more precisely, to neuro-transmitters and their mechanism of action.
The brain consists of a complex network of billions of neurons (nerve cells). All higher brain functions are dependent on neurons communicating with each other by release and uptake of various neuro-transmitters (signaling molecules).
A single neuron makes thousands of connections with neighboring neurons, connections that allow the passage of information from cell to cell. At these specialized points of contact information transfer is facilitated by the neuronal release of signal molecules, called neurotransmitters, which then bind to specific receptor molecules on the recipient cell.
Neurons can be divided into subsystems based upon the neuro-transmitter used, such as the monoaminergic, cholinergic and glutamatergic systems. These subsystems are found in specific parts of the brain and are essential for maintaining various body functions including mental health.

Prof. Kullander explains that there is a well-established link between imbalances of the monoaminergic and cholinergic subsystems and the development of neurological and mental disease. “So far, researchers have been unable to identify any common denominator between the monoaminergic and cholinergic systems. We have, however, recently discovered a molecule referred to as VAAT, which is present in both monoaminergic and cholinergic neurons and takes part in the regulation of neurotransmitter release. We are consequently in the process of examining the relationship between VAAT and mental health”.

Basic research may lead to new treatments.
The research could have a major impact on future drug development, but it is also of great importance for increasing our fundamental understanding of how the brain works, and how mental illness develops. As a consequence of its enormous complexity, understanding the nervous system requires carefully conducted basic research into neuro-transmitters, how they are made and what happens when their release is withheld or delivered in excess. This basic knowledge is a prerequisite for the development of effective treatments – including novel drugs – for abnormalities in the nervous system.

“Mice lacking VAAT exhibit several signs of brain disorders. For example, they are more prone to developing epilepsy. After cocaine or amphetamine treatment, the mice’s neural activity is increased, in a fashion that is similar to that which occurs in various types of drug addiction. We are now working to generate a clearer picture of how VAAT affects neuronal communication by examining this protein’s function in more detail, and in particular how signal molecules are released and reabsorbed in the cell when the protein is active. One of our aims is to explore VAAT as a drug target for development of novel treatments that can help restore imbalances in the brain”.

Raising awareness is most important
Klas Kullander’s research team has a further aim of identifying those substances, which aside from neurotransmitters, can be linked to VAAT and thus may also be important for neuronal communication.
“To achieve this, we are using advanced methods to track changes in nerve cell communication, including uptake and release of various signaling molecules. Developing new pharmaceuticals is important, but in order to generate high quality drugs, we also need to increase our understanding of how the nervous system works and how it affects the brain’s higher functions”, concludes Prof. Kullander.