Forming the ‘right’ type of neurons in the brain

14 February 2013

Ball-and-stick model of serotonin

Image: Ball-and-stick model of serotonin, C10H12N2O.

Different types of nerve cells, or neurons, are formed in the brain and spinal cord depending on levels of a protein called Ascl1, according to new research from the Medical Research Council's National Institute for Medical Research (now part of the Francis Crick Institute).

One of the subtypes of neuron the scientists investigated makes serotonin, a neurotransmitter that is implicated in depression, anxiety and many other conditions. Understanding how these neurons are produced in the right place and quantities in the brain has the potential to improve understanding of these debilitating diseases.

When the brain and spinal cord form, different types of neurons are produced in specific locations. This is controlled by signalling molecules - or chemical messengers - that turn genes on and off to control the type of neuron being made. There are usually a few such signalling molecules that work together to make a specific subtype of neuron. But sometimes the same combination appears to specify very different types of neuron - and until now, scientists didn't know why.

An example is the two subpopulations of cells analysed in this study - the first are in the brain and make the neurons that produce serotonin, while the second are in the spinal cord and produce so-called V3 interneurons. These play a role in walking and running. Both groups of cells express the same combination of signalling molecules to turn the same genes on and off.

James Briscoe and colleagues at NIMR worked with teams from the University of California, Los Angeles (UCLA)and Kyoto University in Japan to find out just how the different neurons are made, using various molecular biology techniques.

They discovered that one particular protein, called Ascl1, was present at high levels in the cells in the brain but low levels in the spinal cord. The team went on to show that the spinal cord cells could make either type of neuron when the Ascl1 level was altered. The level of Ascl1 in both the brain and spinal cord cell populations is regulated by a well known signalling molecule called retinoic acid.

Dr Briscoe said: "Defects in serotonin play a role in common psychiatric disorders including depression and anxiety disorders, and SSRI (selective serotonin reuptake inhibitor) drugs like prozac affect serotonin levels. Defects in the serotonin system have also been suggested to contribute to neurological conditions including autism spectrum disorders.

"This is why it's so important to understand how serotonin-producing neurons are produced in the right place and in the right numbers in the brain. This knowledge has the potential to help understand several neurological and psychiatric disorders and could eventually contribute to new types of therapies. For instance, the findings could eventually help to find a way to produce these neurons artificially from stem cells."

The paper, Retinoid acid specifies neuronal identity through graded expression of Ascl1, was published in Current Biology.

  • Levels of a protein called Ascl1 determine the specific type of nerve cells that are formed in the brain and spinal cord, say Medical Research Council scientists.
  • The team studied groups of cells in the brain and in the spinal cord that make neurons that release serotonin - which plays a role in conditions such as depression and anxiety - and neurons that are involved in walking and running.
  • Understanding how the neurons that produce serotonin are produced in the right place and the right quantities will improve understanding of disorders related to this important brain chemical, and could eventually help improve treatments for related disorders.