Source: Vanderbilt University
Researchers
are one step closer to understanding the physiology of antidepressant
action in the brain. They have confirmed that even when brain cells are
not active, they trigger protein production that affects the function of
cells and neural circuits.
The
work was conducted in the labs of Ege Kavalali, professor and acting
chair of the Department of Pharmacology and William Stokes Chair in
Experimental Therapeutics, and Lisa Monteggia, professor of
pharmacology.
“It
is surprising to see that brain cells without activity initiate gene
transcription,” said Monteggia, also Barlow Family Director of the
Vanderbilt Brain Institute.
“Among
our most interesting findings, we show that it isn’t a huge number of
genes that were changed by an activity-independent mechanism, however
these genes are often involved in activating other downstream genes.”
The
work looks at Brain-Derived Neurotrophic Factor, a growth factor
critical for how antidepressants act. This work shows for the first time
that, independent of activity, BDNF expression can still be regulated.
This new understanding builds on Monteggia’s latest research into how
the drug ketamine acts as an antidepressant and its short- and long-term
effects. It also took shape from previous research in the Kavalali lab
that examined the crucial role of spontaneous neurotransmission in the
brain.
WHY IT MATTERS
Depression,
which the World Health Organization says costs $1 trillion annually in
lost productivity, affects 264 million people around the world. Current
treatments are not effective in approximately half of patients, and
depression’s treatment-resistant population is at far higher risk of
suicide. Monteggia is conducting this functional research to find ways
to mitigate unnecessary and preventable loss of life.
Watch Video: https://youtu.be/-Ac5cHQvWGY
Credit: Vanderbilt University
Basic
science research like Monteggia and Kavalali’s lays the groundwork for
understanding why the body malfunctions and how medications work. By
proposing a testable hypothesis that results in new understanding of the
brain’s fundamental process, scientists can engage in smarter drug
development with the goal of delivering faster or longer-lasting
treatment options.
WHAT’S NEXT
Monteggia
plans to build on a number of angles and techniques to show the broader
perspective and impact of gene expression in the brain. Her team is
creatively dissecting the mechanistic process of the growth factor BDNF
in the brain, with the ultimate goal of extending ketamine’s long-term
effects with fewer side effects. She also is looking into why the drug
may not have an effect for some, to build different therapies for
treatment-resistant patients.
FUNDING
This work was supported by National Institutes of Health grants GM008203, MH081060
282
and MH070727 and MH066198. The work was further supported by a NARSAD
Young Investigator Grant from the Brain and Behavior Research Foundation
and by the Vanderbilt Brain Institute.
About this neuroscience research news
Author: Marissa Shapiro
Source: Vanderbilt University
Contact: Marissa Shapiro – Vanderbilt University
Image: The image is in the public domain
Original Research: Open access.
“A subthreshold synaptic mechanism regulating BDNF expression and resting synaptic strength” by Ege Kavalali et al. Cell Reports