By now you’re familiar with the idea that mental function is based on spiking and secretion. Both processes involve many kinds of proteins. You’ve already encountered an important kind, the receptor molecules that sense neurotransmitter. These sit in the outer membrane of a neuron, partially protruding from the exterior of the cell. (Remember the kid floating in the inner tube?) Earlier I described the binding of a neurotransmitter molecule with a receptor as being like the insertion of a key into a lock. The metaphor goes even further for some receptors, which are a combination of a lock and a door. A small tunnel threads through the receptor molecule, connecting the inside of the neuron to the outside, but it’s blocked by a doorlike structure most of the time. When the neurotransmitter binds to the receptor, the door opens for an instant, and electrical current can momentarily flow through the tunnel. In other words, the neurotransmitter acts like a key that opens a door, allowing electrical current to flow between the inside and outside of the neuron.
In general, we use the term ion channel for any type of protein containing a tunnel that passes electrical current through the membrane. (Ions are the electrically charged particles that conduct electricity in aqueous solutions.) Many types of ion channels are not receptors. Some of them enable the neuron to generate spikes; others have subtler effects on the electrical signals traversing neurons. If your genome contains an abnormal DNA sequence for a receptor or ion channel, it could be bad news for brain function. A disease caused by a defective DNA sequence for an ion channel is called a “channelopathy.” Malfunctioning ion channels can lead to the uncontrolled spiking that we call epileptic seizures.
There are other types of proteins that package neurotransmitter into vesicles, as well as proteins that help release the contents of the vesicles into the synaptic cleft when triggered by a spike. Other proteins help degrade or recycle the neurotransmitter in the cleft, preventing it from lingering too long or drifting off to other synapses. This list is only the tip of the iceberg; it does not do justice to the vast array of proteins that serve spiking and secretion. Defects in any of these proteins could lead to brain disorders.
The possibilities for malfunction go way beyond that, however. On top of their present-day effects, defective genes might have made their mark in the past, when they caused the development of the young brain to go awry.
Roughly speaking, the brain grows and develops in four steps. Neurons are created, or “born,” through the division of progenitor cells, migrate to their proper places in the brain, extend branches, and make connections. Disruption of any of these steps can lead to an abnormal brain.
What happens if the creation of neurons does not proceed successfully? In the city of Gujrat in Pakistan, there is a shrine to a seventeenth-century holy man named Shua Dulah. For centuries, babies born with abnormally small heads have been left at this shrine. In Pakistan they are known as chuas, which translates as “rat people,” probably because their faces protrude in a somewhat ratlike way. The chuas are sometimes exploited by chua masters, who send them out to beg and then take the proceeds. The people tell various myths to explain the existence of chuas. One is the gruesome story that chuas are created by evil people who place clay or metal caps around the heads of babies, thereby retarding the growth of their brains.
In reality, the chuas are born with the disorder of congenital microcephaly. In the purest form, microcephaly vera, the only abnormality appears to be reduced brain size at birth. The cortex is smaller, but the pattern of folds and other architectural features are roughly normal. Not surprisingly, given the smaller cortex, microcephaly vera is accompanied by mental retardation.
Researchers have found that defects in a number of genes (with names like microcephalin or ASPM) can cause microcephaly vera. These genes encode proteins that control the birth of cortical neurons. Defects in them reduce the number of neurons and cause microcephaly. Because there are two copies of every gene, it’s possible to carry one defective copy without showing any symptoms; the single correct copy is enough to make the brain grow normally. But when two carrier parents each pass on a defective copy to their child, he or she is born with microcephaly. This event would normally be rare, but in Pakistan it happens more frequently because of the high rate of intermarriage between cousins. (Since cousins are genetically related, it’s more likely for them both to be carriers than it is for two people chosen at random.)
The second step of brain development, the migration of neurons to their proper places, can also be disrupted. In the disorder of lissencephaly (from the Greek roots for “smooth brain”), the cortex lacks the folds that normally give it a wrinkled appearance, and possesses other structural abnormalities visible in a microscope. The condition is usually accompanied by severe mental retardation and epilepsy. Lissencephalies are caused by mutations in genes that control neuronal migration during gestation.
These two steps in brain development occur in the prenatal brain. By the time a baby is born, the creation and migration of neurons are virtually complete. You may have heard that you were born with all the neurons that you will ever have. (There are only a few areas of the brain in which neurons still continue to be created after birth.) But this does not mean that brain development is over. Neurons continue to grow branches well after birth. This process is called the “wiring” of the brain, since axons and dendrites resemble wires. Axons have to grow the most, since they are much longer than dendrites. Imagine the tiny growing tip of an axon, known as a “growth cone” for its roughly conical shape. If a growth cone were blown up to human size, its travels would take it to the other side of a city. How is the growth cone able to navigate such long distances? Many neuroscientists study this phenomenon, and they’ve found that the growth cone acts like a dog sniffing its way home. The surfaces of neurons are coated with special guidance molecules that act like scents on the ground, and the interstitial spaces between neurons contain drifting guidance molecules that act like scents in the air. Growth cones are equipped with molecular sensors and can “smell” the guidance molecules to find their destination. The production of these molecules and their sensors is under genetic control. That’s how genes guide the wiring of the brain.
If axons don’t grow properly, “miswiring” results. Consider the corpus callosum, a thick bundle of 200 million axons connecting the left and right hemispheres of the cerebrum. In rare individuals, the callosum is either completely or partially missing. Fortunately, the impairments are much milder than in microcephaly. Such miswiring could be caused by defects in many genes, including those that control axon guidance.
For most of its journey through the brain, an axon grows straight, like the trunk of a tree. Once the growth cone reaches its final destination, the axon starts to branch. Scientists have reason to think that this final branching might not be so tightly controlled by genes. If this is the case, the detailed branching pattern of a neuron is largely random, although its overall shape might be genetically determined. Likewise, trees in a pine forest look similar because they come from the same genetic plan. No two trees match exactly branch for branch, however, because growth also involves randomness and is influenced by environmental conditions.
As the wires of the brain are laid down, neurons connect with each other by creating synapses. I hypothesized earlier that the process of synapse creation is random, happening with some probability whenever neurons contact each other. There is also room for genetic control, because neurons of different types might recognize each other through molecular cues and “decide” on that basis whether to connect. (I’ll talk later about neuron types.)
So the initial connectome produced by very early development appears to be largely a product of genes and randomness. Scientists are still studying their relative contributions. According to one theory, genes exert their influence mostly by controlling how the brain wires up. Genes roughly determine the shape of a neuron, the region over which it extends branches. If there is an overlap between the regions spanned by two neurons,
there is potential for connection between them. But whether they actually connect is not determined by genes. At first, it depends on random encounters of branches within the genetically defined regions, and on random creation of synapses at these encounters. But as development proceeds, experiences also start to shape the connectome. How exactly does this happen?
New synapses are created at a staggering rate in the infant brain. In Brodmann area 17 alone, over half a million per second are produced between two and four months of age. To accommodate the synapses, neurites increase in both number and length. Figure 25 illustrates the dramatic growth of dendritic branches from birth to two years of age.
Figure 25. Dendrite growth from birth to age two, followed by pruning
I cautioned in Chapter 5 against thinking of adult learning as purely synapse creation. The same is true of the young brain, for development also destroys connections. When you were two years of age, you had far more synapses than you have now. By adulthood, the number of synapses has dropped to 60 percent of its peak during the toddler years. A similar rise and fall holds for the branches of neurons. Dendrites and axons grow exuberantly at first, but some branches are later pruned away (compare the last two panels of Figure 25).
Why does the brain create so many synapses, only to destroy many of them later? Actually, many so-called creative acts are misnamed, because they involve both creation and destruction. When I’m writing an article, I focus first on getting all my thoughts out onto the page, even if the writing is embarrassingly bad. During this phase, the words increase in number. After a rough draft is complete, further rewriting or editing often shortens the piece. The final article ends up having fewer words than the draft. As the saying goes, perfection is achieved not when there is nothing left to add, but when there is nothing left to take away.
Perhaps the early connectome is like a rough draft. I said above that the initial wiring and the creation of connections are guided by genes but also subject to randomness. And earlier I mentioned the theory that synapse elimination in the adult brain is driven by weakening, which in turn is driven by experience. By the same arguments, experience is likely to be the main driver of synapse elimination in the developing brain. And perhaps the elimination of many synapses from a branch leads to its pruning. These destructive processes refine the rough draft to produce the adult connectome.
This scenario is slightly misleading, however, because it suggests that creation and destruction occur in two distinct phases. The writing analogy clarifies why this is implausible. While working on a rough draft, I both add and remove words. There is net word creation because additions outnumber deletions. It’s the other way around in the later phase of refinement, when the total number of words is decreasing. So it would be a mistake to think that before age two it’s only synapse creation that occurs, and thereafter it’s only synapse elimination. Net creation occurs early and net elimination occurs later, but both processes happen throughout life. Even in adulthood, when the total number of synapses remains roughly constant, both creation and elimination are taking place.
If synapse creation is mostly random while synapse elimination is driven by experience, shouldn’t enriched cages cause synapse number to decrease in rats? Recall the finding of William Greenough and other researchers (mentioned in Chapter 5)—that synapses increase in number. We can only speculate, but here’s one plausible scenario. Let’s suppose that synapse elimination does happen at a greater rate in the brain of an enriched-cage rat, because it is learning more, but then, to replace the eliminated synapses, the brain steps up the creation of new ones. If creation more than compensates for elimination, the result is a net increase in synapse number. In this speculation, the increase in synapse number is the effect of learning rather than its cause.
The oxymoron creative destruction was central to the Austrian economist Joseph Schumpeter’s theory of economic growth and progress. Its first word referred to the creation of new companies by entrepreneurs, and its second to the destruction of inefficient companies by bankruptcy. Brain development, writing an article, and economic growth all involve an intricate interplay between creation and destruction. Both processes are required for complex patterns of organization to evolve. When seen in this light, it verges on futile to measure progress by counting the total number of synapses in a brain, words in an article, or companies in an economy. It’s the organization of the brain that matters, not the number of synapses.
By now you should have some appreciation for the intricacies of brain development. There are plenty of ways for such a complex process to go wrong. Disruption of the earliest steps of development, the creation and migration of neurons, is expected to cause abnormalities that are easy to see, such as microcephaly and lissencephaly. But disruption of the later steps of development could lead to connectopathies, disorders of neural connectivity. The total number of neurons and synapses would be normal, but they would be connected in a less than ideal way.
Remember the story of the Cray-1 supercomputer, which contained hundreds of thousands of wires totaling 67 miles in length? Remarkably, the first time it was powered up, it worked properly. The workers who built it had succeeded in connecting every single wire correctly. Your brain is far more complex, containing millions of miles of “wire.” It’s a wonder that any brain can ever develop correctly at all.
As I mentioned earlier, the corpus callosum fails to develop in rare individuals. This connectopathy is visible in an MRI scan because the callosum is ordinarily so large. But given our inability to see brain connectivity clearly, it’s likely that the vast majority of connectopathies remain undiscovered. These will be revealed as our technologies for finding connectomes advance.
Earlier I zeroed in on the most puzzling aspect of autism and schizophrenia—the lack of a clear and consistent neuropathology. Studies of twins convinced researchers years ago that autism and schizophrenia have some basis in faulty genes. But exactly which of the tens of thousands of genes are faulty? Most researchers now suspect that many of the culprits are somehow involved in brain development. Autism and schizophrenia are said to be neurodevelopmental disorders, in which the brain fails to grow normally. They are fundamentally different from neurodegenerative disorders like Alzheimer’s disease, in which an originally normal brain starts to fall apart.
What is the evidence behind this suspicion? The case is more clear-cut for autism, as its symptoms are detected in early childhood. Whatever the neuropathology may be, it must have emerged during gestation and infancy, when the brain was growing most rapidly. Earlier I mentioned that autistic children have larger brains on average. Looking at brain growth over time reveals a more complex picture. The autistic brain is slightly smaller than average at birth, larger than average from age two to age five, and average again by adulthood. In other words, the rate of brain growth is abnormal in autistic children. This suggests a developmental abnormality, but conclusive proof would require identifying a clear and consistent neuropathology that emerges in the womb or during infancy.
In the first half of the twentieth century, researchers did not believe that schizophrenia was neurodevelopmental. They hypothesized that the schizophrenic brain was normal during childhood and that it started to degenerate in late adolescence or young adulthood, triggering the first episode of psychosis. But they failed to find neuropathologies that should accompany a degenerating brain, so the hypothesis had to be abandoned.
Today many researchers speculate that schizophrenia, like autism, is a neurodevelopmental disorder. It turns out that many schizophrenics experienced slight delays in learning to talk, move, and socialize, so perhaps their brains were already slightly abnormal in childhood. Their brain development might even have veered off course in the womb: Statistical studies suggest that pregnant mothers exposed to famine or viral infection are more likely to give birth to children who later develop schizophrenia.
So here’s what researchers believe: Autism and schizophrenia are caused by some neuropathology,
which is caused by abnormal brain development, which is caused by some combination of abnormal genetic and environmental influences. Neuroscientists are just beginning to find the genes, which could help them close in on the relevant developmental processes. This sounds encouraging, but I’m embarrassed to admit that the most important question has still not been answered: What is the neuropathology? Without data, theories have abounded. Since these are far too numerous to review exhaustively, I’ll focus on the one that makes the most sense to me—the theory that autism and schizophrenia are connectopathies.
Recall that the autistic brain grows faster than normal in early childhood. The overgrowth is somewhat greater in the frontal cortex than in other lobes, perhaps because too many connections are created between neurons there. In addition, researchers speculate that too few connections are created between the frontal cortex and other regions of the brain.
It’s distressing to realize that this theory of autism is based on phrenological evidence and couched in phrenological terms. As I’ve mentioned, the enlargement of the autistic brain is only statistical, governing only averages. Diagnosing autism in an individual child based on the size of the brain or its regions would be grossly inaccurate. Statements about “too many” or “too few” connections are just as crudely phrenological as “too large” or “too small.” If autism is caused by a connectopathy, the difference will probably be found in the organization of connections, rather than in their overall number. The connectopathy would be invisible to our current technologies; hence the failure to find a clear neuropathology for autism.
Could schizophrenia, too, be caused by a connectopathy? Here the most tantalizing evidence comes from studies of synapse elimination. Earlier I mentioned that adults have fewer synapses than babies, but I did not describe exactly when the reduction occurs. Researchers have found that synapse number declines rapidly after the peak in infancy, stays roughly constant during childhood, and drops rapidly again in adolescence. Perhaps something goes wrong in the schizophrenic brain during this second reduction. The defect is probably not as simple as too few or too many synapses, as that kind of neuropathology would have been detected by now. Maybe the wrong synapses are eliminated, and this pushes the brain over the edge to psychosis.
Connectome Page 12
