Making and breaking connections in the brain
The links between nerve cells, called synapses, allow us to
learn and adapt, and hold clues to conditions such as autism,
schizophrenia and more
If you were to take a human brain and toss it in a blender —
not that you should — the resulting slurry of cells wouldn't be
special in the way that the human brain is. No thoughts, no
worries, no wonder or awe.
That's because it’s the connections between those cells that
make the brain so amazing. By sending electrical signals
from nerve cell to nerve cell within a great network of
connections, the brain creates thoughts as mundane as
“Where are my keys?” or as profound as “I think, therefore |
am.”
The links between neurons are called synapses. What exactly
is a synapse, and what happens there?
It’s basically a connection: one cell talking to another. A brain
cell, or a neuron, has a large main body, with small strands
sticking out. So one neuron, the transmitter, uses a really thin
strand called an axon. A second neuron, the receiver, can
receive contacts along its main body, or along strands that
branch out like a tree, called dendrites. When the axon tip of
a transmitter connects to a receiver, that’s a synapse.
Neurons run on electricity. If an electrical signal passes
down an axon, its tip releases chemicals called
neurotransmitters into the synapse.
These neurotransmitters tell the receiver cell to either
activate its own electrical charge, which sends the signal to
the next neuron in the chain, or tell the receiver cell to stay
quiet.A diagram shows a synapse where two types of projections
that extend from nerve cells, the axon and dendrite, connect.
Some of the molecules at synapses are also shown.
When a nerve cell communicates with another nerve cell, the
message is transmitted from the tip of an axon, the long
slender arms that extend from the cell's main body. This
axon terminal releases chemical messengers known as
neurotransmitters (blue dots), into the space between the
two cells, called the synaptic cleft. Receptor proteins ona
receiving cell's dendrite — another branch-like arm — pick up
these neurotransmitters, which tell the receiving cell whether
to stay quiet or send the message along. This much-
simplified depiction also shows a handful of the thousands
of kinds of proteins found at synapses, including voltage-
gated ion channels that help nerves send electrical signals,
and transport proteins that shuttle molecules in and out of
the cells.
But it’s not as simple as one receiver for every transmitter.
For example, in the frontal cortex — the part of the brain
housing abilities such as language that distinguish us from
other animals — the neurons look beautiful, like trees. They
can have 10,000 or more synapses on their branching
dendrites, each of which may receive information from a
different cell.The activity at those thousands of inputs gets added up to
cause the neuron to fire — or not — and that’s how
information is transferred in the brain. This kind of
information transfer, across complicated networks made by
the 120 billion neurons in the human brain, allows for
complex thoughts.
Axons and dendrites can move around, especially when the
brain is young. The way in which they connect individual
neurons creates the network pathways. During development,
the 100 trillion synapses in the human cortex form at a rate
of an estimated 10,000 every 15 minutes! Together, all these
synapses create a giant network. And that gives us
consciousness.
When | started, we didn’t know anything about how synapses
form. | developed a technique to study dendrite growth. What
we realized is that the shape of neurons and dendrites is
dependent on activity at synapses. That is, if the brain isn't
getting input — from the senses and the environment — and
responding with conversations across the network, then the
neurons won't build the right receivers, and the brain won't
develop properly.
Synapses are very small but incredibly complex molecular
machines made up of proteins that guide, maintain and
strengthen the connections. One of the biggest advances,
over the last 20 years, has been our identification of the
tremendous number of proteins that make up these
connections. Biochemists estimate there are thousands of
different, distinct proteins at each synapse.The amazing diversity of these proteins is what allows the
brain to tune the strength and stability of synapses, allowing
us to think complex thoughts and build memories.
We've learned that if there is a genetic mutation that changes
the function of one of these proteins, it can contribute to
disorders such as autism, schizophrenia and depression.
We've come to think of these conditions as synapse
disorders, or synaptopathies.
In a developing fetus or a baby, neurons have been thought
to form lots of connections willy-nilly, as described by the
delightful phrase “exuberant synaptogenesis.” How does this
process build an organized brain?
When neurons are born in the fetal brain, they migrate to their
proper position. A simplified way of thinking about it is that
some move to the cerebrum which is involved in jobs like
speech and reasoning, some to the cerebellum, which is
involved in coordinating movement, and some to the brain
stem where automatic body actions like breathing are
rooted. Once positioned, the axons then follow chemical
trails to target areas, either in the same part of the brain or
elsewhere.
In textbooks, it says that once they are in the basic target
area, axons form exuberant connections; then the excess
synapses are pruned only later in development. But we now
know there are molecules that limit synapse formation to
start with, that the initial formation is more tightly controlled.
Most brain neurons develop before birth, but the brain
continues to mature long after that, with the neurons making
and breaking an astonishing number of connections, called
synapses.The neurons seen in this video were isolated from the cortex
of a newborn mouse and grown in a dish where they were
imaged every 30 minutes between days six and eight after
birth. The slender cellular projections called axons (red) are
seeking the branchlike dendrites (green) of neighboring
neurons, in order to form connections.
The ability of the brain to strengthen or weaken synapses
depending on how active they are is often referred to as
“plasticity.” What is plasticity and why is it important?
Plasticity means the brain can change, for example by
altering connections in its networks. Without plasticity, we
wouldn't be able to learn or adapt to our environment. When
you learn something, you have electrical activity going
through different circuits. Those electrical impulses change
the strength of specific connections, making them either
stronger or weaker.
For example, if you learn that “hola” means “hello” in Spanish,
certain synapses will become stronger. This results from
changes in the various proteins making up the synapse.
Scientists can see this when they mimic learning in slices of
brain in lab dishes, and even in living animals. Dendrites have
little bumps, called spines, that act as signal receivers. After
learning, these spines get larger, and they are more likely to
stick around. That kind of change is part of plasticity.
Little kids are great at absorbing new information and skills.
As adults, we're often not so good at this. How does
plasticity change with age?The brains of young animals have a lot of plasticity. For each
ability in the brain, such as picking up a language, there's a
critical period in which learning is easy. That critical period is
when the brain is making lots of changes. If you look at
those dendrite spines in a young brain, they’re moving
around like crazy.
But when you look in an adult brain, the spines don’t move
very much. That’s because material that acts like glue comes
in and holds the neurons in place. The critical period for each
brain region closes at a different time. For example, the
critical period for language development starts to close
around age 5. But the brain’s ability to make rational
judgments isn't fully mature until about age 25.
So the connections are pretty stable in adults, but plasticity
doesn’t completely disappear. In adults, it’s not so much
about adding or deleting connections, but tuning the strength
of synapses, using all those synapse proteins.
One of the great mysteries is why adults lose that ability to
learn so easily. In some cases, like parts of the visual system
in frogs and goldfish, this plasticity doesn’t disappear.
Scientists are trying to understand what happens in those
creatures. If we could reopen the critical period in someone
whose nerves are damaged or deteriorating, maybe we could
regrow connections.
To study synapses, scientists first tackled the
neuromuscular junction, where certain neurons meet up with
muscles to control movement. Where did researchers go
from there?In the 1990s and early 2000s, the field was completely
dominated by neuromuscular junction studies. It's a much
simpler synapse than those in the brain. We learned a lot.
But in the brain, synapses are much more diverse. Focusing
on the brain became possible with the development of
techniques that allowed us to take neurons out of the brain
and watch, in a dish, as they form networks. So we can start
to assess how synapses form, function and disappear in the
complex networks they form even outside of the brain.
What we've discovered is there are huge differences between
the brain and the neuromuscular junction. There are many,
many more diverse types of synapses in the brain, and more
kinds of neurotransmitters. It makes the brain much more
complicated — not to diminish the complexity of the
neuromuscular junction! — and super-interesting.
Researchers have also discovered a new class of molecules
that hold the two sides of the synapse together. Why are
these important?
These molecules span the gap between the two sides of the
synapse, holding the transmitting and receiving cells
together like zippers, and they’re really important for synapse
formation and elimination.
It turns out that mutations that alter many of these “zipper”
molecules make synapses dysfunctional, and are associated
with brain disorders including epilepsy, Down syndrome and
Alzheimer's disease. For example, defects in the gene for a
zipper protein called neuroligin were linked to autism; then
researchers found mutations in the same gene in people with
schizophrenia.But you also can have these mutations and no brain disorder.
One of the burning questions right now is, what causes
somebody with a zipper protein mutation to manifest
symptoms and why do distinct sets of symptoms (i.e. autism
vs. schizophrenia) show up in different people with the same
mutations?
| think these zipper proteins may turn out to be even more
interesting than other parts of the synapse. Scientists now
want to understand: How can we develop drugs to fix the
dysfunctional synapses?
The brain has been thought to be somewhat isolated from
the body’s immune system. Yet you and others are now
studying the role of immune cells and molecules in the brain.
What do they do?
There is tremendous excitement about a particular kind of
immune cell called microglia. These cells clear away dead
cells and other used-up materials in the brain. Microglia can
eliminate synapses by eating them. We know they’re involved
in brain diseases such as Alzheimer’s, because they are
switched to their active, anti-infection state in people with
those conditions. But it's still a puzzle exactly how they
contribute.
I've been studying brain functions of immune molecules
called MHC1. These molecules stick off of the surfaces of
almost all cells. Their traditional job is to tell the immune
system that those cells are part of the body, and not
something to attack. MHC1 molecules are also involved in
synaptic plasticity. They prevent synapse formation early on,
so they make brain development less exuberant and more
tightly controlled.| also think MHC1 molecules are involved in how chemicals
or infections affect brain development. I’m part of a group
studying how infections in pregnant women exacerbate the
baby’s risk for eventual autism spectrum disorder or
schizophrenia. In one project, we're studying the offspring of
mother mice after the mothers were exposed to a virus-like
substance that provokes an immune response. The offspring
mice have more MHC1, and fewer synapses, in their brains
than control animals. This suggests that infections that
engage the immune system can change brain circuitry
through changing levels of immune molecules at synapses.
On the one hand, the fact that infections can alter brain
development is scary. On the other hand, most of the time
infections don't affect the brain. If we can better understand
how, when and why the immune system regulates brain
development, we might one day be able to develop
medicines to change the immune response and fix what's
going on, or going wrong, in the brain.