Major depression or chronic stress can
cause the loss of brain volume, a condition that contributes to both
emotional and cognitive impairment. Now a team of researchers led by
Yale scientists has discovered one reason why this occurs — a single
genetic switch that triggers loss of brain connections in humans and depression in animal models.
The findings, reported in the journal Nature Medicine, show
that the genetic switch known as a transcription factor represses the
expression of several genes that are necessary for the formation of
synaptic connections between brain cells, which in turn could contribute
to loss of brain mass in the prefrontal cortex.
How the study was done
"We wanted to test the idea that stress causes a loss of brain synapses
in humans," said senior author Ronald Duman, the Elizabeth Mears and
House Jameson Professor of Psychiatry and professor of neurobiology and
of pharmacology. "We show that circuits normally involved in emotion, as
well as cognition, are disrupted when this single transcription factor
is activated."
The research team analysed tissue of depressed
and non-depressed patients donated from a brain bank and looked for
different patterns of gene activation. The brains of patients who had
been depressed exhibited lower levels of expression in genes that are
required for the function and structure of brain synapses.
Lead author and postdoctoral researcher H.J. Kang discovered that at
least five of these genes could be regulated by a single transcription
factor called GATA1. When the transcription factor was activated,
rodents exhibited depressive-like symptoms, suggesting GATA1 plays a
role not only in the loss of connections between neurons but also in symptoms of depression.
Duman theorises that genetic variations in GATA1 may one day help
identify people at high risk for major depression or sensitivity to
stress.
"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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