The brain’s immune cells are hyperactive in people who are at risk of developing schizophrenia, as well as during the earliest stages of the disease, according to a new study by researchers at the MRC Clinical Sciences Centre in London. The findings, published today in the American Journal of Psychiatry, suggest that inflammatory processes play an important role in the development of the disease, and raise the possibility that it could be treated with drugs that block or reduce this cellular response.
Schizophrenia is a severe mental illness that affects about 1 v 100 lidé, and is characterised by symptoms such as auditory and visual hallucinations, and delusions of paranoia or grandeur. People with the disease may hear voices in their head, or believe that other people are controlling their thoughts, or are trying to hurt them.
Although the causes of schizophrenia are unknown, inflammatory processes have already been implicated in it. Patients with schizophrenia, and those deemed to be at high risk of developing the disorder, exhibit elevated levels of small, pro-inflammatory proteins called cytokines, and this is associated with reduced gray matter volume; and post-mortem examinations of brain tissue show that activated microglial cells are present in higher numbers in people with schizophrenia compared to others, particularly in the frontal and temporal lobes.
Microglia are the brain’s resident immune cells, which form its first line of defence against infection and injury. In any such event, damaged neurons emit a distress signal, which activates microglial cells and attracts them to the damaged or infected site, where they proceed to engulf and neutralize pathogens, cellular debris, and anything else that is potentially harmful or no longer needed. This occurs by a process called phagocytosis, whereby a segment of the microglial cell membrane first envelops the undesired material, then pulls it inwards and internalizes it completely.
Peter Bloomfield and his colleagues wanted to know if the activity of microglial cells is altered in the early stages of schizophrenia. oni rekrutovali 14 patients diagnosed with schizophrenia, a 14 at risk of developing the disease, from mental health centres in south London, a 28 zdravý, age-matched controls for comparison, via posters and newspaper advertisements.
The researchers used neurochemical imaging to measure the level of microglial activity. První, they injected all their participants with a radioactive ‘tracer’ molecule called [11C]PBR28. This binds in a highly selective manner to TSPO, a transporter protein synthesized mostly, but not exclusively, by microglial cells, which ramp up their production of it when activated. They then carried out positron emission tomography (PET) scans to visualize the distribution and intensity of tracer binding in the participants’ brains, in order to determine the extent of microglial activation.
The scans revealed that binding of the radioactive tracer was far more widely distributed in the brains of patients with schizophrenia, and in those at risk of the disease, compared to the controls. Klíčové, distribution of the tracer was closely related to symptom severity, with those patients presenting with more severe symptoms. And one participant in the at-risk group, who exhibited the highest level of tracer binding, went on to have their first psychotic episode, and developed full-blown schizophrenia, shortly afterwards.
This confirms earlier findings that microglial activation is elevated in the brains of patients with schizophrenia, and provides what the researchers believe is the very first evidence of elevated microglial activity in people who are at risk of developing schizophrenia, and of an association between greater microglial activation and greater severity of symptoms. While it’s possible that excessive microglial activation is merely a protective response, the results strongly suggest that inflammatory processes are involved in the disease, and may even contribute to its development.
We now know that microglia eliminate unwanted synaptic connections in the same way that the remove pathogens and damaged cells, engulfing them by phagocytosis. This process, called synaptic pruning, occurs extensively throughout the developing brain, and as a matter of course in the healthy adult brain, which continuously makes and breaks synapses. Major pruning also occurs during a protracted period that extends from late adolescence through to early adulthood.
This pruning eliminates some 40% of the total number of synapses in the brain, and is critical for maturation of the frontal cortex, which is involved in so-called executive functions such as planning and decision-making. It makes adolescence and early adulthood a highly sensitive period, during which people are more susceptible to various kinds of mental illness. Schizophrenia typically begins in this stage of life, and so may occur as a result of aberrant pruning.
“My hunch is that this is what’s going on, and that microglial activation is part of the disease pathology, as opposed to a protective response,” says senior author Oliver Howes. “We know that people with schizophrenia have loss of synapses, and that microglia play a role in synaptic pruning. If pruning goes to excess, or goes wrong, it could lead to major problems in brain function, and that may be what we’re seeing here.”
The results suggest that blocking or reducing microglial activation, with drugs that are already being used to treat other conditions, might alleviate the symptoms of schizophrenia. “We think microglia may be activated in response to infection or head trauma, but then start pruning too much, leading to the onset of the illness,” says Howes, “and now we’re planning a clinical study that reduces microglial activation to see if that reduces symptoms. Mimo to, we’d like to take it to a full-scale clinical trial and look at potentially preventing onset altogether.”
Bloomfield, P. S., a kol. (2015). Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. Am J. Psychiat. DOI: 10.1176/appi.ajp.2015.14101358. [Abstraktní]
guardian.co.uk © Guardian News & Media Limited 2010