Many scientists believe that strengthening synaptic connections could
offer a way to treat those diseases, as well as age-related decline in brain function. To that end, a team of MIT researchers has developed a new way to grow synapses
between cells in a laboratory dish, under very controlled conditions
that enable rapid, large-scale screens for potential new drugs.
Using their new technology, the researchers have already identified
several compounds that can strengthen synapses. Such drugs could help
compensate for the cognitive decline seen in Alzheimer’s, says Mehmet
Fatih Yanik, the Robert J. Shillman (1974) Career Development Associate
Professor of Electrical Engineering at MIT and leader of the research
team. Yanik and his colleagues described the technology in the Oct. 25
online edition of the journal Nature Communications.
Lead author of the study is MIT postdoc Peng Shi. Other authors are
MIT graduate students Mark Scott and Zachary Wissner-Gross; Stephen
Haggarty, Balaram Ghosh and Dongpeng Wan of Harvard University; and
Ralph Mazitschek of Massachusetts General Hospital, who developed and
analyzed the potential drug compounds screened in the study.
At a synapse, a neuron sends signals to one or more cells by
releasing chemicals called neurotransmitters, which influence the
activity of the recipient cell. Scientists can induce neurons grown in a
lab dish to form synapses, but this usually produces a jumble of
connections that is difficult to study.
In the new setup devised by Yanik and his colleagues, presynaptic
neurons (those that send messages across a synapse) are grown in
individual compartments on a lab dish. The compartments have only one
opening, into a tiny channel that leads to another compartment. The
presynaptic neuron sends its long axon through the channel into the
other compartment, where it can form synaptic connections with cells arranged in a grid. “That way we can induce synapses in very well-defined positions,” Yanik says.
Using this technique, the researchers can create hundreds of
thousands of synapses on a single lab dish, then use them to test the
effects of potential drug compounds. This technique can detect changes
in synaptic strength with 10 times more sensitivity than existing
methods.
In this study, the researchers created and tested variants of a type
of molecule known as an HDAC inhibitor. HDACs are enzymes that control
how tightly DNA is wound inside the cell nucleus, which determines which
genes can be copied and expressed. HDAC inhibitors, which loosen DNA
coils and reveal genes that had been turned off, are now being pursued
as potential treatments for Alzheimer’s and other neurodegenerative
diseases.
The researchers’ goal was to find HDAC inhibitors that specifically turn on genes that enhance synaptic connections.
To determine which had the strongest effects, they measured the amount
of a protein called synapsin found in the presynaptic neurons. Those
tests yielded several HDAC inhibitors that strengthened synapses, with
the best one improving synapse strength by 300 percent.
Several HDAC inhibitors had little effect on synaptic strength,
demonstrating the importance of finding HDAC inhibitors specific to
synaptic genes.
The new technology offers a significant improvement over existing
methods for growing synapses and studying their formation, says Matthew
Dalva, associate professor of neuroscience at Thomas Jefferson
University, who was not part of the research team. “Right now we know so
little about synapse formation, so this could open new doors,” he says.
In future studies, this system could also be used to examine the
connections between specific types of neurons obtained from different
regions in the brain, such as those thought to be impaired in people
with autism. Yanik plans to make the technology available to other research groups interested in doing such studies.
From medicalxpress.com