Working memory: How you keep things ‘in mind’ over the short term

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Two new studies uncover key players responsible for learning and memory formation

neurosciencestuff:

One of the most fascinating properties of the mammalian brain is its
capacity to change throughout life. Experiences, whether studying for a
test or experiencing a traumatic situation, alter our brains by
modifying the activity and organization of specific neural circuitry,
thereby modifying subsequent feelings, thoughts, and behavior. These
changes take place in and among synapses, communication junctions
between neurons. This experience-driven alteration of brain structure
and function is called synaptic plasticity and it is considered the
cellular basis for learning and memory.

Many research groups across the globe are dedicated to advancing our
understanding of the fundamental principles of learning and memory
formation. This understanding is dependent upon identifying the
molecules involved in learning and memory and the roles they play in the
process. Hundreds of molecules appear to be involved in the regulation
of synaptic plasticity, and understanding the interactions among these
molecules is crucial to fully understand how memory works.

There are several underlying mechanisms that work together to achieve
synaptic plasticity, including changes in the amount of chemical
signals released into a synapse and changes in how sensitive a cell’s
response is to those signals. In particular, the protein BDNF, its
receptor TrkB, and GTPase proteins are involved in some forms of
synaptic plasticity, however, very little is known regarding when and
where they are activated in the process.

By using sophisticated imaging techniques to monitor the
spatiotemporal activation patterns of these molecules in single
dendritic spines, the research group led by Dr. Ryohei Yasuda at Max
Planck Florida Institute for Neuroscience and Dr. James McNamara at Duke
University Medical Center have uncovered critical details of the
interplay of these molecules during synaptic plasticity. These exciting
findings were published online ahead of print in September 2016 as two
independent publications in Nature (1, 2).

A surprising signaling system within the spine

In one of the publications (Harward and Hedrick et al.), the authors
identified an autocrine signaling system – a system where molecules act
on the same cells that produce them – within single dendritic spines.
This autocrine signaling system is achieved by rapid release of the
protein, BDNF, from a stimulated spine and subsequent activation of its
receptor, TrkB, on the same spine, which further activates signaling
inside the spine. This in turn leads to spine enlargement, the process
essential for synaptic plasticity. In other words, signaling initiated
inside the spine goes outside the spine and activates a receptor on the
external surface of the spine, thereby evoking additional signals inside
the spine. This finding of an autocrine signaling process within the
dendritic spines surprised the scientists.

What are the consequences of the autocrine signaling within the spine?

The second publication (Hedrick and Harward et al.) reports that the
autocrine signaling leads to activation of an additional set of
signaling molecules called small GTPase proteins. The findings reveal a
three-molecule model of structural plasticity, which implicates the
localized, coincident activation of three GTPase proteins Rac1, Cdc42,
and RhoA, as a causal feature of structural plasticity. It is known that
these proteins regulate the shape of dendritic spines, however, how
they work together to control spine structure has remained unclear. The
researchers monitored the spatiotemporal activation patterns of these
molecules in single dendritic spines during synaptic plasticity and
found that all three proteins are activated simultaneously, but their
activation patterns differed significantly. One of the differences is
that RhoA and Rac1, when activated, spread beyond the stimulated spine
to the surrounding dendrite, which facilitates plasticity of surrounding
spines. Another difference is that Cdc42 activity was restricted to the
stimulated spine, what seems to be necessary to produce spine-specific
plasticity. Furthermore, the autocrine BDNF signaling is required for
activation of Cdc42 and Rac1, but not for RhoA.

Unprecedented insights into the regulation of synaptic plasticity

These two studies provide unprecedented insights into the regulation
of synaptic plasticity. One study revealed for the first time an
autocrine signaling system and the second study presented a unique form
of biochemical computation in dendrites involving the controlled
complementation of three molecules. According to Dr. Yasuda,
understanding the molecular mechanisms that are responsible for the
regulation of synaptic strength is critical for understanding how neural
circuits function, how they form, and how they are shaped by
experience. Dr. McNamara noted that disorder of these signaling systems
likely underlies dysfunction of synapses that cause epilepsy and a
diversity of other diseases of the brain. Because hundreds of species of
proteins are involved in the signal transduction that regulates
synaptic plasticity, it is essential to investigate the dynamics of more
proteins to better understand the signaling mechanisms in dendritic
spines.

Future research in the Yasuda and McNamara Labs is expected to lead
to significant advances in the understanding of intracellular signaling
in neurons and will provide key insights into the mechanisms underlying
synaptic plasticity and memory formation and brain diseases. These
insights will hopefully lead to the development of drugs that could
enhance memory and prevent or more effectively treat epilepsy and other
brain disorders.