Research paves the way for a new treatment against schizophrenia

AGENCIA FAPESP/DICYT A number of studies conducted at the University of Campinas’s Biology Institute (IB-UNICAMP) in São Paulo State, Brazil, have indicated that oligodendrocyte dysfunction may have a key role in the development of schizophrenia. Oligodendrocytes are specialized brain cells that provide important support for neuronal activity.

The research was performed with support from FAPESP. The principal investigator was Daniel Martins-de-Souza, a professor at IB-UNICAMP.

These recent results were published in the European Archives of Psychiatry and Clinical Neuroscience and Frontiers in Cellular Neuroscience. Additionally, a review article on the subject was published in NPJ Schizophrenia, an open-access, online-only journal linked to Nature Publishing Group.

“If we can build an understanding of exactly what happens differently in the oligodendrocytes of patients with schizophrenia, we can think about new therapeutic approaches,” Martins-de-Souza told Agência FAPESP. “The treatments available today focus on neurons. But failures in communication between neurons may be a consequence of oligodendrocyte dysfunction.”

He explained that schizophrenia is commonly considered a brain disconnectivity disorder: in other words, for reasons not yet fully understood, the cells of the central nervous system do not communicate as they should. As a result, patients suffering from schizophrenia typically experience difficulty in distinguishing between reality and imagination, and display mental confusion, among other symptoms.

“When it was discovered that there was a problem with the pattern of brain cell connections, most researchers set out to understand what was happening to the patient’s neurons,” he said. “Until the early 1990s, another type of brain cells, known as glial cells, was considered mere brain tissue whose function was just to assist the neurons.”

In addition to oligodendrocytes, two other types of glial cell exist: astrocytes and microglia. According to Martins-de-Souza, studies performed over the last 20 years have shown that these cell types also have important biological roles. Oligodendrocytes, for example, produce myelin, a mixture of lipids and protein that is indispensable to information exchange among neurons.

“Neurons have long ‘arms’, called axons, along which they exchange electrical impulses to communicate,” he said. “Many axons are covered with a layered myelin sheath, which accelerates the transmission of electrical signals. This can be compared to the insulating sheath used on electric wiring to prevent short circuits.”

Recent findings by the group have also suggested that oligodendrocytes are responsible for supplying energy to axons so that the latter can accurately perform highly complex tasks.

Structural and functional differences

Imaging studies performed in the 2000s showed that the brains of schizophrenics have fewer oligodendrocytes than healthy individuals.

“When the human genome mapping project was completed, several transcriptome studies were conducted. Some showed that genes relating to neuron myelination were differentially expressed in patients with schizophrenia,” Martins-de-Souza said. “Around 2005, our group was the first to show that the proteins produced by oligodendrocytes were also differentially expressed in these patients.”

Since then, the IB-UNICAMP group has investigated how brain functioning in these patients is affected by deficits in ten myelin-associated proteins produced by oligodendrocytes, especially myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP).

“We’ve found evidence that they are differentially expressed in both brain tissue and the cerebrospinal fluid that bathes the central nervous system. Patients with schizophrenia have more MBP, the main protein component of myelin, in their cerebrospinal fluid, suggesting there may be a loss of myelin sheath, whose components become soluble in this fluid.”

Masters student Verônica Cereda conducted a recent study in which post-mortem brain tissue from healthy individuals was compared with tissue from schizophrenics. She found that the corpus callosum, the region of the brain with the most oligodendrocytes, displayed differential expression of a number of proteins produced by these cells.

In vitro evidence

To understand what happens to each type of brain cell in patients with schizophrenia, the group cultured neurons, oligodendrocytes, astrocytes and microglia separately in vitro. The cultures were treated with MK-801, a drug that inhibits glutamatergic transmission (information exchange between cells mediated by the neurotransmitter glutamate), as glial-neuronal interactions are impaired in schizophrenia.

“We found impaired pathways for energy supply in astrocytes and especially in oligodendrocytes,” Martins-de-Souza said. “Interestingly enough, we didn’t find differences in neurons. This result reinforces the hypothesis that oligodendrocyte dysfunction plays a key role in schizophrenia.”

In an ongoing project supported by a scholarship from FAPESP, as part of Juliana Silva Cassoli’s postdoctoral research, the group is trying to obtain a deeper understanding of oligodendrocyte energy metabolism.

In Cassoli’s study, cultured cells will be induced to overexpress aldolase, an enzyme that helps to break down certain sugars to produce energy, while its expression will be inhibited in a separate group of cells. The effects on oligodendrocytes in each case will be compared.

“We want to see how aldolase overexpression or inhibition affects cell viability and protein expression,” Martins-de-Souza said. “Then we’ll culture oligodendrocytes together with neurons to find out whether the myelination process is altered by aldolase modulation.”

In his opinion, the most important contribution of these studies would be evidence that protein production by oligodendrocytes in patients with schizophrenia is not sufficient for the brain to function properly. “Our research will show that oligodendrocytes and their markers can also be therapeutic targets,” he said.