Researchers have shown that an extremely rare type of brain cell plays a central role in brain dysfunction linked to schizophrenia in a genetic mouse model. Suppressing the activity of these cells reverses several symptoms – opening the door to more targeted treatments.
Schizophrenia remains one of the most challenging mental disorders to treat, because the exact mechanisms in the brain that cause the symptoms are still not known.
Now, researchers show that an extremely rare type of brain cell is closely linked to the symptoms that make schizophrenia so debilitating.
When the researchers dampened the activity of these cells in mice, several of the symptoms disappeared – a finding that points directly to a possible source at the core of the disease.
The crucial question now is whether humans have the same mechanism and whether this could open the door to more targeted treatments than those available today.
“Current treatments for cognitive symptoms among people diagnosed with schizophrenia are inadequate. We need to understand more about what causes these cognitive symptoms, which stem from disturbances in brain development. Our study may be the first step towards a new, targeted treatment that can prevent cognitive symptoms,” says a researcher behind the study, Konstantin Khodosevich, Associate Professor at the Biotech Research & Innovation Centre, University of Copenhagen, Denmark.
The research has been published in Neuron.
A small group of cells causes major problems in the brain
The researchers examined mice carrying a schizophrenia-associated genetic mutation known as the 15q13.3 microdeletion and focused on a very specific and extremely rare group of brain cells: the cortical somatostatin-expressing GABAergic projection neurons – a type of inhibitory nerve cell that acts as the brain’s brake pedal and normally helps to keep the activity of other nerve cells under control.
“These brain cells are extremely rare – they make up only 0.001% of all brain cells – but impaired function of these cells causes mice to develop several symptoms reminiscent of schizophrenia, including disturbed sleep.”
The researchers worked specifically with a mutation called the 15q13.3 microdeletion, in which a small piece of genetic material is missing. In humans, this mutation is associated with schizophrenia, epilepsy, autism and other nervous system disorders.
“More and more data indicate that schizophrenia is linked to poor sleep and that sleep deprivation worsens the symptoms through cognitive deterioration. We wanted to test this in this mouse model because it is also well known that people with this genetic defect – the 15q13.3 microdeletion – have sleep problems,” explains Konstantin Khodosevich.
He elaborates that there are only a handful of traits that can realistically be examined in studying psychiatric disorders in animals. For instance, disturbed sleep can be investigated as a symptom of the disorder – but not whether the mice experience delusions.
Mutation makes cells hyperactive – but only in adulthood
Mutations in the genes related to the brain cells under study made them hyperactive – meaning that they send too many signals at the wrong times – a disturbance that first appears in young adult animals and not in the early stages of development.
This observation is interesting because it is well known that schizophrenia can lie quietly in human genes throughout childhood and then emerge in adulthood.
“For a long time, the brain can compensate for these defective cells, but at some point it can no longer do this, and then the symptoms appear. But in theory, it should be possible to prevent the symptoms until that point,” says Konstantin Khodosevich.
The research shows how these specific brain cells develop and change their activity from the fetal stage to adulthood.
The research also shows that mice carrying these mutations sleep extremely poorly.
Suppressing these cells dampened several symptoms in mice
However, the most striking finding is that the researchers actually suppressed the activity of these cells by using chemogenetics, in which specific receptors in the cells are activated or inhibited with a benign chemical compound, enabling the researchers to switch the cells on and off as needed.
The researchers found that suppressing the activity of these cells improved the mice’s sleep – a key symptom of schizophrenia.
“Future research will show whether it can also suppress other symptoms,” explains Konstantin Khodosevich.
Can the same mechanism also be found in humans?
Konstantin Khodosevich hopes that the research will become clinically relevant.
This may well be the case if researchers can show that inhibiting the activity of these cells in mice not only reduces sleep problems but also alleviates other symptoms of schizophrenia.
The next step will be to investigate whether these same rare cells also play a role in humans. If so, the research could point directly to a new, targeted way of preventing and treating schizophrenia.
“This is a really interesting discovery that some very rare cells in the brain appear to be at the core of the problems associated with schizophrenia,” concludes Konstantin Khodosevich.
