How Depression Shrinks the Brain

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Certain brain regions in people with major depression are smaller and less dense than those of their healthy counterparts. Now, researchers have traced the genetic reasons for this shrinkage.

A series of genes linked to the function of synapses, or the gaps between brain cells crucial for cell-to-cell communication, can be controlled by a single genetic "switch" that appears to be overproduced in the brains of people with depression, a new study finds.

"We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated," study researcher Ronald Duman, a professor of psychiatry at Yale University, said in a statement.

Transcription factors are proteins that help control which genetic instructions from DNA will be copied, or transcribed, as part of the process of building the body's proteins.

Shrinking brain

Brain-imaging studies, post-mortem examinations of human brains and animal studies have all found that in depression, a part of the brain called the dorsolateral prefrontal cortex shrinks. The neurons in this region, which is responsible for complex tasks from memory and sensory integration to the planning of actions, are also smaller and less dense in depressed people compared with healthy people. [Top 10 Stigmatized Health Disorders]

Duman and his colleagues suspected that these neuronal abnormalities would include problems with the synapses, the points where brain cells "talk" to one another. At synapses, neurons release neurotransmitters that are picked up by their neighbors, carrying signals from cell to cell at rapid speed.

The researchers conducted gene profiling on the postmortem brain tissue of both depressed and mentally healthy subjects. They found a range of genes that were significantly less active in depressed people's dorsolateral prefrontal cortexes, particularly five related to synaptic function: synapsin 1, Rab3A, calmodulin 2, Rab4B and TUBB4.

Synaptic damage

These genes are all involved in either the chemical signaling that occurs at synapses or the cellular recycling and regeneration processes that keep the synapse-system humming.  All five are regulated by a single transcription factor called GATA1, which was overproduced in depressed brains.

The researchers activated GATA1 in the brains of rats and found that the factor decreased the complexity of the long, branchlike projections, or dendrites, of brain cells. These projections are the telephone lines that carry synaptic messages, integrating all the information a cell receives.

Extra GATA1 also increased depression-like behavior in the rats. For example, when given a swimming task, rats with extra GATA1 stayed immobile in the water longer, a signal of despair, than normal-GATA1 rats, the researchers report today (Aug. 12) in the journal Nature Medicine.

The researchers believe the damage could be a result of chronic stress, and they hope the findings lead to new depression treatments.

"We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies," Duman said.

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