Star-shaped cells: a clue to differences in schizophrenia pathology?

Dr Vibeke Sørensen Catts is a schizophrenia researcher. Her interests lie in exploring the biological factors that help brain cells grow and die, and how these pathways might be altered in schizophrenia. Here she describes her discovery that certain types of brain cells are inflamed in some people with schizophrenia. This recent finding opens new understanding of what goes wrong in this disorder and how it might be treated.

Dr Vibeke Catts

Dr Vibeke Catts

One of the problems with trying to understand a serious mental illness like schizophrenia is that it doesn’t manifest in the same way in all people. In fact, there is a wide range of symptoms and brain abnormalities across its sufferers, who number 1 out of every 100 people.

My colleagues and I were able to turn this variability to some advantage in our research, by deliberately grouping the people we studied according to the molecular features associated with their illness.

A previous study in the Schizophrenia Research Laboratory had found that one third of people with schizophrenia had high levels of biological markers of inflammation in their brain. The identification of this ‘high inflammatory’ group contributed to an increased understanding among researchers that inflammation contributes to schizophrenia pathophysiology, but the ‘how’ of this process was still not well understood.

Inflammation is a protective bodily response to injury or illness, and in the short term is important for normal processes like muscle growth, but is detrimental over a chronic time course. During inflammatory processes, certain specialised cells are activated, releasing chemicals that regulate symptoms such as swelling and pain. In the brain, this process is known as gliosis, and involves extra growth of the ‘support cells’ of the brain, such as microglia and astrocytes. Earlier studies have shown that microgliosis is present in the brains of people with schizophrenia, but it has not been determined how this links to the increased inflammation in the brain that we had observed in some schizophrenia patients.

To see whether the activation of astrocytes (named for their star-shaped appearance) might be the missing link between a general marker of inflammation such as microgliosis and the other inflammatory markers observed in the brain of this group of schizophrenia patients, we measured a protein called GFAP in the prefrontal cortex of people with schizophrenia. GFAP stands for glial fibrillary acidic protein, and it is a marker for astrogliosis.

Taking a closer look at the brain

We did not find an overall difference in GFAP between people with schizophrenia and healthy controls. This didn’t surprise us, since there is so much variability between schizophrenia patients, and because we had previously observed inflammation in the brain of only a subset, rather than all of the schizophrenia patients. However, when we measured GFAP in that ‘high inflammatory’ subset, this group had increased evidence for astrogliosis than the ‘low inflammatory’ group of schizophrenia patients. Furthermore, the shape of the astrocytes in the ‘high inflammatory’ group was different to the ‘low inflammatory’ group.

Questions, answers, and . . . more questions

Our findings are interesting, but highlight the need for further research. Is the response of astrocytes lower in some people with schizophrenia than in other brain illnesses such as Alzheimer’s disease where inflammation and astrogliosis is abundant? Or perhaps the response starts out normally, but is halted over time due to other factors at play in the illness? For example, antipsychotic medications used to treat schizophrenia symptoms may inhibit the process of gliosis, and so an individual’s exposure to these medications needs to be considered in trying to sort out the contribution of these cellular processes to disease.

Regardless, a continuing discussion of whether gliosis plays a major role in schizophrenia is important. Schizophrenia is considered a disorder of aberrant brain development rather than of brain degeneration. However, our data suggest that it is premature to rule out the idea that some individuals experience a different course of illness such that neurodegeneration associated with inflammation is an integral part of what goes wrong. This would in turn inform tailored treatment development for these people.

Visible neuroscience

Imaging techniques enable neuroscientists to learn about the structure and function of cells in the nervous system. Here, Dr Zoltán Rusznák shares some captivating images of the brain and how they were made.

Neurons are the building block cells of the brain and spinal cord, communicating with each other through synapses to regulate nervous system function. Relating the shape, size, and location of neurons to their function is important in understanding mechanisms in brain health and disease. However, because neurons are small, three-dimensional, and embedded among many other cells in the nervous system, special techniques are required to be able to see them. The following pictures show neurons in the cochlear nucleus, which is the part of the brain that decodes sound information from the ear.

Stacking up to localise sound

Globular bushy cells illuminated by a fluorescent stain

Globular bushy cells illuminated by a fluorescent stain

What’s in this picture? Globular bushy cells are neurons in the cochlear nucleus that act as sophisticated timing devices. They measure tiny delays in how quickly a sound reaches both ears, which is the basis of how we localise the source of a sound.

How was it made? The picture on the left was taken with a camera attached to a microscope. It shows a round bushy cell body in the middle of a single, very thin slice of brain tissue – a slice only 0.06% of the thickness of a grain of salt! The right-hand picture is a stack of 40 images taken from successive slices of the same piece of brain tissue – imagine a stack of salami coming out of a deli slicer. The image stack results in a view of much greater depth, so that a second bushy cell body becomes visible, as well as a detailed view of the synaptic nerve terminals, indicated by the several bright green structures on the cell bodies.

Putting the puzzle together

Giant neurons illuminated by a fluorescent stain

Giant neurons illuminated by a fluorescent stain

What’s in this picture? ‘Giant neurons’ of the cochlear nucleus receive sound information from the ear and help to localise the source of sound from a single ear.

How was it made? These pictures are also made from stacks of single images, like in the previous picture. However, since the giant neurons are so, well, giant, many adjacent image stacks have to be assembled like a puzzle in order to capture the many branching nerve endings. Each square in the pictures corresponds to a single field of view of the microscope.

Merging muscarinic receptors

Granule cells and muscarinic receptors illuminated by fluorescent stains

Granule cells and muscarinic receptors illuminated by fluorescent stains

What’s in this picture? These small round neurons in the cochlear nucleus are called granule cells. Neurons have proteins on their surface called receptors that respond to chemical messengers and transmit signals throughout the neuron. Sometimes we want to know the specific type and location of receptors that a messenger binds to in order to transmit its signal.

How was the picture made? Different fluorescent dyes are used to distinguish the receptor from the rest of the neuron. The left-most image shows green, bead-like dots that indicate the presence of a particular type of receptor called a muscarinic M3 receptor in a slice of brain tissue. The middle picture is taken from the very same piece of brain tissue, but the tissue is instead stained blue to define the nucleus of the granule cells. When the green and blue images are merged (right-hand picture), the green dots are showed to be surrounding the blue cell nuclei. This tells us that the receptors are located on the surface of the granule cells, and suggests that these receptors mediate the effects of certain neurochemical messengers in the cochlear nucleus. This information is helpful to determine how hearing works and what might go wrong in auditory disorders.

Of squiggly lines and schizophrenia

Dr Jason Bruggemann is investigating new ways of identifying children at risk of developing schizophrenia.

I am relatively new to schizophrenia research, so I was surprised by the sheer diversity of people I have met who have schizophrenia – men and women from a wide variety of backgrounds with distinct personalities who don’t conform to any particular stereotype. While the disease affects them in different ways, however, they have all described the significant challenges that schizophrenia has posed for them and their families.

Schizophrenia is a neurodevelopmental disorder that typically begins during late adolescence or early adulthood. Healthy development during adolescence involves large-scale reorganisation and restructuring of the brain, including changes to the delicate excitatory/inhibitory balance of the brain’s neurotransmitter systems and underlying brain structure. This process seems to go awry for people with schizophrenia. Environmental factors like stress also appear to contribute to the onset of the disease.

Dr Jason Bruggemann

Dr Jason Bruggemann holds an EEG ‘net’, made up of wires and electrodes.

We know that early diagnosis and treatment can significantly improve long-term outcomes and help minimise the damaging effects of schizophrenia. Hence, current research is focused on potential ways of identifying children at risk of developing schizophrenia. Our colleague Dr Kristin Laurens and her team from Kings College London are currently evaluating a combination of factors as potential early markers, including subtle peculiarities of speech and movement, lower IQ and poorer academic achievement, disturbances in social, emotional, and behavioural functioning, and subclinical psychotic-like experiences such as occasionally hearing voices that nobody else can hear.

At NeuRA, we are conducting research into another potential marker of schizophrenia risk called the mismatch negativity (MMN). The MMN is an index of the brain’s electrical response to changing patterns of sounds. It’s derived from a measure of the electrical activity of the brain called the electroencephalograph (EEG), more commonly known as ‘brainwaves’. The raw EEG signal may look like just a bunch of squiggly lines running across the computer screen but, once analysed, the resulting data can help us better understand patterns of normal and abnormal brain function.

An example of a raw EEG

The squiggly lines of a raw EEG read out.

In adults with schizophrenia, the size of the MMN has been related to disease severity, ability to function in the wider-community (functional outcome), and grey matter volume loss in the frontal and temporal brain regions. The MMN is usually smaller in adults with chronic schizophrenia compared with typical individuals. In light of this, we recently investigated whether a group of children who may be at increased risk of schizophrenia (based on having some of the risk factors described above or having a first-degree relative with schizophrenia) also have a smaller MMN relative to typically developing children.

Our results showed that although the MMN exhibited by the children at risk of schizophrenia was unlike that of their typically developing peers, it also differed from the smaller MMN observed in adults with schizophrenia. In fact, we found a relative increase in the MMN over the frontal brain region, rather than a decrease!

“If we can reliably identify at-risk children then perhaps we can reduce the burden of schizophrenia for future generations.”

It was difficult for us to interpret this result in the context of what we know about MMN in adults with chronic schizophrenia. We looked at MRI data from an overlapping sample of children, which revealed differences in grey and white matter volume in the same brain regions that produce the electrical activity seen in the MMN. Also, the developmental literature indicates that the MMN tends to be larger in young children compared to adults. This has led us to speculate that perhaps the ‘at-risk’ children are on a different developmental trajectory than their peers. It is possible that this unusual MMN result may reflect the complex interplay between developmental changes and the factors placing these children at higher risk of developing schizophrenia.

It’s essential to conduct long-term follow-up of these potentially at-risk children to establish who goes on to develop schizophrenia and how their MMN changes as they mature. This follow-up work, being completed by our colleague Dr Kristen Laurens, will tell us whether the increased MMN we found in this study may indeed be a useful way of identifying children at risk of developing schizophrenia.

The unique people with schizophrenia that I have met currently live their lives as best they can despite the challenges raised by this condition. If we can reliably identify at-risk children then, with appropriate early treatment, perhaps we can reduce the burden of schizophrenia for future generations.

‘A grown up is a child with layers on’

Evolution is the gradual development of something into a more complex or better form. I witness this everyday as a paediatric neurologist: A newborn is vulnerable and fully dependent on its parents and during childhood movements become smooth and an infant learns to stand, walk and then run. Compared to development in other species, human children take a long time to grow up. Continue reading