Flies with schizophrenia genes respond well to anti-psychotics

Scientists have successfully treated flies displaying behavioural problems linked to newly discovered schizophrenia-associated genes in humans, using common anti-psychotics.

Schizophrenia is a severe long-term mental health condition that is historically poorly understood and treated. It is relatively common, affecting 1-2% of the population, and is known to be up to 80% genetic in origin.

Recent advances in sequencing genomes of people with schizophrenia have identified a list of novel genes and mutations associated with the disease. Many are expressed in the brain and are involved in how neurons communicate with each other by electrical and chemical signals released at synapses.

The research was performed by the first student, Dr Sergio Hidalgo, on the dual PhD program from the Universities of Bristol and the Pontificia Universidad Catolica de Chile. He studied the role of two schizophrenia associated genes on behaviours associated with the disease, using the genetics of the fruit fly, Drosophila.

“We studied two of these schizophrenia-associated genes – one called Rim, which is involved in neurotransmitter release at synapses, and another called CACNA1A and CACNA1B in humans and cacophony in flies, voltage-sensitive calcium channels involved in electrical and chemical signalling in and between neurons. We found that fly Rim mutants showed several behavioural changes seen in people with schizophrenia who may have Rim mutations. These included preferring larger social distances between individuals when in a group and changes in smell or olfaction. We also found the circadian (24-hour body clock) deficits reported in schizophrenia were also present in Rim mutant flies,” said Dr James Hodge, who supervised the research at School of Physiology, Pharmacology and Neuroscience at the University of Bristol.

Treatment with the commonly used antipsychotic, haloperidol, rescued some of the Rim mutant’s behavioural problems.

The second study looked at voltage-gated calcium channels, several of which are major contributors to the risk of developing schizophrenia. The team focussed on the negative symptoms of schizophrenia which include behavioural defects such as impaired memory, sleep and circadian rhythms.

“These symptoms are particularly poorly understood and treated. We found fly cacophony (cac) mutants showed several behavioural features including decreased night-time sleep and hyperactivity similar to those reported in human patients. We also found that loss of cac function in the clock of the fly’s brain decreased their circadian rhythms, while loss of cac function in their memory centre reduced the fly’s memory via a reduction in calcium signalling,” said Dr Sergio Hidalgo.

Two new research papers have come out of the study, published in Translational Psychiatry and Neurobiology of Disease. The research represents important advances in understanding schizophrenia by demonstrating how loss of rim or cac Cav2 channel function causes several disease relevant cognitive and behavioural deficits and underlying reduction in synaptic growth and neuronal calcium transients.

Image credit: Kelsey Thoman

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