Image: Christine Daniloff |
Each
of the brain’s 100 billion neurons forms thousands of connections with other
neurons. These connections, known as synapses, allow cells to rapidly share
information, coordinate their activities, and achieve learning and memory.
Breakdowns in those connections have been linked to neurological disorders
including autism and Alzheimer’s disease, as well as decline of memory during
normal aging.
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 Massachusetts Institute of Technology (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 an online edition of 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 laboratory 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
laboratory 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 laboratory 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%.
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.