The brain is full of mysteries and wonders.
It is the most delicate and complex organ in the human body. Fragile yet powerful, the
brain coordinates the functions of almost all other organs in the human body. It receives
information from all over the body, makes decisions and sends commands to accomplish
necessary tasks. Different regions of the brain are responsible for different functions such
as movements, language, vision, learning, memory and so on. These regions are well
linked to form complicated circuits to process information. A neuron, by an average number
of about 100 billion, is the basic functional unit of the brain. They have very fine structures
called synapses to send information to or receive information from other neurons.
Each neuron can possess as many as 10,000 synapses, which means a neuron can make
as many as 10,000 connections with others. Irregularities in synapse formation or synapse
activity could possibly destroy the very basis of brain functions, leading to brain disorders or
psychiatric diseases.
Seeking for the linkage between synapses and psychiatric diseases, Our group in the Hong
Kong University of Science and Technology has been investigating synapse formation
and synapse function for many years. In this project, we focused on the
hippocampal region of the brain which is associated with
direct learning and memory abilities, and studied the synapses of the hippocampal
neurons using mice and rats as the animal models. By using molecular
markers, we were able to trace the development of the neurons
and stamp the critical time windows for synapse formation and synapse functioning
under a microscope. We found that the proteins, thrombospondin and neuroligin1,
could together accelerate the process of synapse formation, but only during the early
development stage. Accordingly, neuroligins are a critical protein family in the synapse
structure, and help to ligate the synapses from two neurons together. They have been found
to be associated with autism. It is interesting to discover that this accelerating function
only works during early synapse formation, because autism first appears during infancy
or childhood. It implies that early synapse formation can be a target of autism research.
Figure 1. Synapse formation in different time
windows. Cultured rat hippocampal neurons are marked
with fluorescent markers against synaptic proteins PSD-95
(red) and synapsin1 (green) in vitro on days 6, 9, 12, 16 and
20 (from left to right). The yellow puncta signals where the
synapses are.
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Furthermore, we found the mechanism
through which synapses maturate from a newly formed naive synapse into an
active synapse. By culturing hippocampal neurons and other cells together, we were
able to construct a system of artificially-induced synapses and
study the maturation of those new synapses. Taking advantage
of this coculture system and other genetic manipulating techniques, we found that
the protein PICK1 could recruit a critical synapse protein AMPA
receptor onto the naive synapses, thereby accomplishing the synapse
maturation.
Even though our current work is focused on the hippocampus, it is highly possible that
the mechanisms of synapse formation and synapse maturation elucidated in this project
are general across most regions of the brain because the critical proteins we investigated
are all highly expressed in the brain and distributed in most parts of the brain. Some
of these synaptic proteins have long been shown to be involved in psychiatric diseases
and mental retardation. Hopefully we can eventually find the bridge between synapse
construction and brain functions. Only then will we be able to understand how a screw
sunk Titanic.
Dr Jun XIA
Section of Biochemistry and Cell Biology
Division of Life Science
The Hong Kong University of
Science and Technology
jxia@ust.hk
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