Perhaps the most surprising recent finding uncovered by the large collaborative effort on the genetics of schizophrenia is that some of the same genes that create a risk for schizophrenia also create a risk for bipolar disorder. What’s more, a different group of genes that creates a risk for schizophrenia also creates a risk for autism spectrum disorders.
So here we have three different diagnoses—autism, schizophrenia, and bipolar disorder—sharing genetic variants. This overlap suggests that the three disorders have other features in common early in life.
DELETED GENES
One out of every four thousand babies is born with a piece of chromosome 22 missing from its genome. The amount of DNA that is missing can vary, but it usually involves about 3 million DNA building blocks, known as base pairs, resulting in the loss of between thirty and forty genes. Because the missing DNA is from a region near the middle of the chromosome, at a location designated q11, people with the deletion are said to suffer from 22q11 deletion syndrome.
The syndrome can cause highly variable symptoms. Almost everyone with the deletion has abnormalities of the head and face, such as cleft lip or cleft palate, and over half have cardiovascular disorders. They also display cognitive deficits that range from impaired working memory and executive function, as well as mild learning disabilities, to mental retardation. About 30 percent of adults with the syndrome are diagnosed with psychiatric disorders, including bipolar disorder and anxiety disorders. But schizophrenia is by far the most prevalent disorder. In fact, the risk of schizophrenia in a person with 22q11 deletion syndrome is twenty to twenty-five times greater than the risk of schizophrenia in the general population.
To find out which genes might be responsible for the various medical problems associated with the syndrome, scientists looked for an animal in which to model the deletion. It turns out that a segment of DNA in chromosome 16 in the mouse has almost all of the genes present in the q11 region of chromosome 22 in humans. By deleting a different section of the region from different mice, the scientists were able to generate several mouse models of the human syndrome.
The models revealed that the loss of a transcription factor—a protein involved in gene expression—is responsible for many of the non-psychiatric medical conditions suffered by humans, including cleft palate and some heart defects. Many scientists are now using mouse models to determine which specific genes within the 22q11 region, when missing, contribute to schizophrenia. Considering the prevalence of schizophrenia in people with this deletion, the scientists have a good chance of identifying those genes.
In 1990 David St. Clair, then at the University of Edinburgh, and his colleagues described a Scottish family with a high prevalence of mental illness.5 Thirty-four members of the family carry what is known as a balanced autosomal translocation. This means that pieces of two different non-sex chromosomes have broken off and switched places. Of the thirty-four family members who carry this particular translocation, five were diagnosed with schizophrenia or schizoaffective disorder (schizophrenia plus mania and/or depression) and seven with depression.
The researchers identified two genes that are disrupted by the translocation: DISC1 (disruption in schizophrenia 1) and DISC2 (disruption in schizophrenia 2). Although this particular translocation has been found in only one family, that family’s unusually high incidence of psychiatric disorders suggests that these two genes, and other genes close to where the chromosomes broke, may be responsible for psychotic symptoms in schizophrenia and in mood disorders. Two separate groups of researchers found another genetic clue: some polymorphisms in the DISC1 gene occur together frequently and seem to contribute to the risk of schizophrenia.6 So far, studies have been focused on the DISC1 gene because the DISC2 gene does not produce a protein; however, the DISC2 gene is thought to play a role in regulating the DISC1 gene.
Numerous studies in fruit flies and mice have found that DISC1 affects a variety of cell functions throughout the brain, including intracellular signaling and gene expression. DISC1 is particularly important in the developing brain: it helps neurons migrate to their proper location in the fetal brain, to position themselves, and to differentiate into various cell types. Disruption of the DISC1 gene compromises its ability to perform these critical developmental functions.
Taken together, the mouse models show quite clearly that the disrupted functions of the DISC1 gene lead to deficits typical of schizophrenia. In addition, all of the models show changes in brain structure that are similar to the ones observed in people with schizophrenia. Brain-imaging studies of one model, for example, show the enlarged lateral ventricles and smaller cortex seen in people with schizophrenia. Another model shows that disrupting the gene’s function soon after birth produces abnormal behavior in the adult animal. The apparent role of the DISC1 gene in schizophrenia and the findings in mice are consistent with the idea of schizophrenia as a disorder of brain development.
GENES AND EXCESSIVE SYNAPTIC PRUNING
Normal synaptic pruning, in which the brain trims unneeded connections between neurons, is extremely active during adolescence and early adulthood and takes place primarily in the prefrontal cortex. As we have seen, people with schizophrenia have fewer synapses in this area of the brain than unaffected people do, so researchers have long suspected that synaptic pruning is excessive in schizophrenia.
Recently, Steven McCarroll, Beth Stevens, Aswin Sekar, and their colleagues at Harvard Medical School provided further evidence in support of this idea. They also described how and why pruning may go wrong, and they have identified the gene responsible.7
The researchers focused on a particular region of the human genome, a locus called the major histocompatibility complex (MHC). This complex of genes on chromosome 6 encodes proteins that are essential for recognizing foreign molecules, a critical step in the body’s immune response. The MHC locus, which had been strongly associated with schizophrenia in previous genetic studies, contains a gene called C4. The activity of the C4 gene—that is, its level of expression—varies significantly among individuals. The researchers wanted to find out how variations in the C4 gene are related to its level of expression and whether its level of expression is related to schizophrenia.
McCarroll, Stevens, Sekar, and their colleagues analyzed the genomes of more than sixty-four thousand people with and without schizophrenia and found that the people with schizophrenia were more likely to carry a particular variant of the C4 gene known as C4-A. This finding suggested that C4-A may increase the risk of schizophrenia.
Earlier studies had found that proteins produced by genes in the MHC locus play a role in immunity and are involved in synaptic pruning during normal development. This raised a critical question: What exactly is the role of the protein product produced by the C4-A gene? To answer the question, scientists bred mice without the gene. They observed less-than-normal synaptic pruning in these mice, indicating that the protein’s role is to promote pruning and suggesting that too much of the protein leads to excessive pruning. In studies of these mice McCarroll, Stevens, Sekar, and their colleagues also found that during normal development the C4-A protein “tags” the synapses to be pruned. The more active the C4 gene is, the more synapses are deleted.
Together, these studies suggest that overexpression of the C4-A variant leads to excessive synaptic pruning. Excessive pruning during late adolescence and early adulthood—when normal synaptic pruning kicks into overdrive—changes the anatomy of the brain and accounts for both the late onset of schizophrenia and the thinner prefrontal cortex of people with the disorder.
Carrying a gene variant that facilitates aggressive pruning is not enough in itself to cause schizophrenia; many other factors are also at work. But in a small subgroup of people, one specific gene—the C4-A gene—gives rise to anatomical changes that lead to schizophrenia. Thus, McCarroll, Stevens, Sekar, and their colleagues have given us the first real inroad into the etiology of schizophrenia, an inroad that may eventually lead to new treatments. Moreover, i
mportant studies such as these inspire other researchers who are trying to use genetics to advance our understanding of psychiatric disorders.8
MODELING THE COGNITIVE SYMPTOMS OF SCHIZOPHRENIA
Earlier, we learned that excessive dopamine production may contribute to the development of schizophrenia and that antipsychotic drugs produce their effects by blocking dopamine receptors in the mesolimbic pathway. We also learned that brain-imaging studies have found both more dopamine and more D2 receptors in the striatum of people with schizophrenia. Moreover, in at least some people, the greater-than-normal number of D2 receptors may be determined genetically. In light of these findings, Eleanor Simpson, Christoph Kellendonk, and I set out to determine whether an excessive number of D2 receptors in the striatum causes the cognitive symptoms of schizophrenia.9
To do so, we created a mouse model containing a human gene that overexpresses D2 receptors in the striatum. We found that this transferred gene, or transgene, impairs in the mouse the same cognitive processes that are affected in people with schizophrenia. In addition, the mouse lacked motivation, a deficit that is characteristic of the negative symptoms of schizophrenia. But the most interesting result was that whereas the motivational deficits disappeared once the transgene was switched off, the cognitive deficits did not—they persisted long afterward. In fact, the action of the transgene during the period of prenatal development alone was sufficient to cause cognitive deficits in adulthood.
These findings suggest three important new ideas.
First, excessive action of dopamine in the mesolimbic pathway, resulting from an overabundance of D2 receptors, could be the main cause of schizophrenia’s cognitive symptoms—because this pathway connects to the prefrontal cortex, the site of the cognitive symptoms. Second, antipsychotics that block D2 receptors ease the positive symptoms of schizophrenia but have little, if any, beneficial effect on the cognitive symptoms. Why? Because this medication is given too late in development—long after irreversible changes have taken place. Third, because cognitive and negative symptoms are strongly correlated in people with schizophrenia, they may be caused by some of the same factors.
All of these remarkable manipulations—creating deletions, inserting transgenes, and increasing the number of D2 receptors in mice—are just some of the many tools scientists are now using to discover the causes of schizophrenia, depression, and bipolar disorder. In a larger sense, these manipulations are beginning to give us some insights into the relationship of brain science to cognitive psychology, of the relationship of brain to mind.
LOOKING AHEAD
Before moving on to considerations of other brain disorders, it is worth reexamining some of the important contributions research has made to our understanding of the healthy brain from studies of autism spectrum disorders, mood disorders, and schizophrenia.
The importance of brain imaging can scarcely be overestimated. Our understanding of where and how psychiatric and autism spectrum disorders affect the brain has advanced hand in hand with advances in imaging technology. And because imaging studies generally compare the brains of people with and without a particular mental disorder, they have given us additional insights into the healthy human brain as well. Imaging has advanced to the point where it can show us what regions, and sometimes even what neural circuits within those regions, are essential for normal functioning.
Imaging has also confirmed that psychotherapy is a biological treatment—that it physically changes the brain, as drugs do. Imaging has even predicted, in some cases of depression, which patients are best treated with drugs, with psychotherapy, or with both.
We have also seen how critical insights into the nature of depression and schizophrenia came about by accident, when drugs designed to treat another disorder were observed to have an effect on patients with these brain disorders. Subsequent research on how the drugs act in the brain revealed important biochemical underpinnings of depression and schizophrenia and led to better treatments for people with these disorders.
Advances in genetics are uncovering how genetic variations—whether common or rare—create a risk of developing complex brain disorders. Particularly fascinating is the discovery of shared genes that operate in schizophrenia and bipolar disorder, and in schizophrenia and autism spectrum disorders. Such insights into the molecular nature of depression and schizophrenia have also improved our understanding of normal mood and of organized thought.
Finally, we are again reminded of how much we owe to animal models of disease. Genetic studies of social behavior in animals have shown that some of the same genes that contribute to social behavior in animal models also contribute to our own social behavior; mutations in those genes may therefore be involved in autism spectrum disorders. Recent studies of schizophrenia, in particular, have relied heavily on mouse models for vital clues to the causes of this disorder of thought and volition.
In a larger sense, the studies of autism, depression, bipolar disorder, and schizophrenia—and the brain functions they affect—have yielded profound insights into the nature of our mind and our sense of self. These insights are informing a new understanding of human nature and thereby contributing to the emergence of a new humanism.
5
MEMORY, THE STOREHOUSE OF THE SELF: DEMENTIA
Learning and memory are two of the most wondrous capabilities of our mind. Learning is the process whereby we acquire new knowledge about the world, and memory is the process whereby we retain that knowledge over time. Most of our knowledge about the world and most of our skills are not inherent but learned, built up over a lifetime. As a result, we are who we are in good measure because of what we have learned and what we remember.
Memory is part and parcel of every brain function, from perception to action. Our brain creates, stores, and revises memories, constantly using them to make sense of the world. We depend on memory for thinking, learning, decision making, and interacting with other people. When memory is disrupted, these essential mental faculties suffer. Thus, memory is the glue that holds our mental life together. Without its unifying force, our consciousness would be broken into as many fragments as there are seconds in the day.
No wonder we worry about the continued reliability of our memory.
We have seen that disturbances of memory accompany depression and schizophrenia, but what about loss of memory per se? Is memory loss inevitable as we age? Is normal age-related memory loss different from Alzheimer’s disease and other disorders that affect memory?
This chapter first describes what we know about memory, including how we learn and how our brain stores what we have learned as memory. It then considers the aging brain and three neurological disorders that affect memory: age-related memory loss, Alzheimer’s disease, and frontotemporal dementia. Both Alzheimer’s and frontotemporal dementia, as well as Parkinson’s disease and Huntington’s disease, which we will discuss in chapter 7, are thought to be caused in part by faulty protein folding. But before exploring the aging brain and protein folding, let’s touch on different types of memories, how they are created, and where in the brain they are stored.
THE SEARCH FOR MEMORY
Memory is a complex mental function—so complex, in fact, that scientists initially questioned whether it was even possible for memory to be stored in a particular region of the brain. Many thought it was not. However, as we saw in chapter 1, the noted Canadian neurosurgeon Wilder Penfield made an astonishing discovery in the 1930s. When he stimulated the temporal lobe of his epileptic patients prior to surgery (fig. 5.1), some of them seemed to be recalling memories, such as a lullaby their mother used to sing to them or the recollection of a dog chasing a cat.
Figure 5.1. Stimulation points (diamond shapes) on the temporal lobe that elicit auditory memory in the left and right hemispheres of the brain
Penfield had earlier outlined sensory and motor maps of brain function, but memory was a different, more complicated matter. He called in Brenda Milner, an extraordinarily gifted young cognitive psyc
hologist on the staff of the Montreal Neurological Institute, and together they investigated the temporal lobe, particularly its medial (inner) surface, and its role in memory.
One day, Penfield received a telephone call from William Scoville, a neurosurgeon working in New Haven, Connecticut, who had recently operated on a man suffering from severe seizures. That man was H.M. (fig. 5.2), who became one of the most important patients in the history of neuroscience.
Figure 5.2. H.M.
Figure 5.3. Comparison of an intact brain and H.M.’s brain, with part of the medial region of both temporal lobes removed (arrows)
H.M. had been run over by a bicycle rider when he was nine years old. The resulting head injury led to epilepsy. By age sixteen, he had begun having major convulsions. He was treated with the maximum doses of the anticonvulsant medication available at that time, but the medication didn’t help him. Although he was bright, he had great difficulty finishing high school and keeping a job because of his frequent seizures. Eventually, H.M. went to Scoville for help. Scoville inferred that H.M. suffered from scarring of the hippocampal structures lying deep within the temporal lobes. He therefore removed a part of the medial region of the temporal lobe—including the hippocampus—on both sides of H.M.’s brain (fig. 5.3).
The operation essentially cured H.M.’s epilepsy, but it left him with severe memory disturbance. Although he remained the polite, gentle, calm, and pleasant young man he had always been, he had lost the ability to form any new long-term memories. He remembered people he had known for many years before the operation, but he did not remember anyone he had met since the operation. He couldn’t even learn how to get to the bathroom in the hospital. Scoville invited Milner to study H.M., and she ended up working with him for twenty years. Yet each time she walked into the room, it was as if H.M. were meeting her for the first time.
The Disordered Mind Page 11