Drosophila as a high-throughput in vivo genetic model to study Antipsychotic drugs

Significance 

Schizophrenia is a severe long-term mental health condition that is historically poorly understood and treated. It is relatively common, affecting one to two per cent of the population, and is known to be up to 80 per cent 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.

Scientists have successfully treated flies displaying behavioural problems linked to newly discovered schizophrenia-associated genes in humans, using common anti-psychotics. The research led by Dr James Hodge from the School of Physiology, Pharmacology and Neuroscience at University of Bristol studied the role of two schizophrenia associated genes on behaviours associated with the disease, using the genetics of the fruit fly, Drosophila.

They 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. Strikingly, 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.

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 a number of disease relevant cognitive and behavioural deficits and underlying reduction in synaptic growth and neuronal calcium transients.

It is apparent from this study that these behaviours are caused by changes in calcium signalling, shape of synapses and their release of neurotransmitter. Along with the ability to return these behaviours to normal with a commonly used schizophrenia drug, these studies establish Drosophila as a high-throughput in vivo genetic model to study the Cav channel and neurotransmitter release pathophysiology related to schizophrenia.

The next step is to understand how rim and different calcium channels act together at synapses to regulate behaviours affected by schizophrenia. By testing drugs or treatments directed at these targets we will develop a deeper understanding of therapies for schizophrenia, and how they work.

According to the authors, understanding the complexity of schizophrenia etiology could help us to develop new and more effective treatments. By showing that some molecular mechanisms are conserved between species, the authors propose the use of flies as a new platform for drug testing.

Drosophila as a high-throughput in vivo genetic model to study Antipsychotic drugs - Medicine Innovates

About the author

Dr James Hodge

School of Physiology, Pharmacology and Neuroscience

University of Bristol

We are interested in how neural circuit activity underlies behaviour including circadian rhythms, sleep, memory and movement. We study these using Drosophila, molecular genetics, electrophysiology and optogenetics. We study the fundamental biology of behaviour and how they are affected by ageing, drugs and diseases including Alzheimer’s, Parkinson’s, Down’s, schizophrenia and neuropathies. We also studying the effect of neonicotinoid insecticides on fly and bee circadian rhythms and sleep.

Reference

Sergio Hidalgo, Jorge M. Campusano, James J. L. Hodge. Assessing olfactory, memory, social and circadian phenotypes associated with schizophrenia in a genetic model based on Rim. Translational Psychiatry, 2021; 11 (1) DOI: 10.1038/s41398-021-01418-3

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