Histone Monoaminylation In The Cns: Novel Insights Into The Cause And Treatment Of Human Depression

Could chemicals in the brain cause depression by affecting which genes are involved in different brain processes?

The project

We know the brain circuits that carry serotonin – a chemical that helps send messages between different parts of the brain – play a big part in causing and treating depression. But we don’t know exactly how – and this lack of knowledge is holding us back.

So Dr Ian Maze and his team are considered whether serotonin alters the way the brain works through an ‘epigenetic’ process – essentially causing cells to switch different genes in the brain on and off.

They looked at:

• How serotonin affects the way that genes in certain brain cells work and use information
• Whether this process is different in people who have depression
• Whether serotonin switching genes on and off is involved in depression
• How anti-depressants affect what’s happening, so we can build our knowledge of exactly how they work.

The process

The project was structured around three main objectives:

1. Investigate the biochemical mechanisms of histone serotonylation.
2. Examine the role of H3 serotonylation in depression-associated gene transcription in dorsal raphe nucleus (DRN) neurons, using a mouse model of chronic social defeat stress (CSDS).
3. Explore how this novel modification regulates depressive-like behaviours.

The team developed and validated chemical tools, including highly specific antibodies and viral vectors, to study and manipulate histone serotonylation in neurons. They used both in vitro and in vivo models, including genome-wide assessments and behavioural studies in mice. The research also included analysis of post-mortem human brain tissue from individuals with and without depression