Fruit flies contribute to the understanding of the brain

Inês Sousa is a paediatrician and tells about her research project where fruit flies play a central role in understanding and studying of molecular aspects of brain disorders.

You are starting your PhD in the Netherlands. Can you tell us what your research project is about?

– In my project I focus on a group of genes that have been related to neurodevelopmental/ESSENCE disorders including ASD and ADHD, but also language impairment and intellectual disability, and try to find common mechanisms for these disorders.

– I started working under supervision of Annette Schenck, at the Radboud University Medical Centre in Nijmegen, the Netherlands. In this lab the focus is on neurogenetics and exploring the fruit fly Drosophila as a model organism to study and understand molecular aspects of brain disorders.

Can you give us some background to this research area and how you came to be involved in it?

– As a paediatrician working in a neurodevelopment clinic, I realised that I needed to know more about what was wrong with my patients in order to provide better treatment. The brain is a very complex organ. Solutions that have been useful to understand heart disease might not be suitable to understand neuropsychiatric disorders. I felt there was a need for a model system that I could use to work with dysregulated genes, affected neuronal systems, and which could be used to test different drugs. In this way I hope to better understand mechanisms of disorders and contribute to offering the most specific and effective treatment to my patients.

– After discussion with several professors, including Christopher Gillberg I started at The Gulbenkian Institute for Science, in Portugal, with the aim of finding such a model system. I was expecting to use a computer science tool, or a brain imaging device that could show me how the brain would work at a molecular level. I was disappointed to see that technology is not yet at this level, and that statistical analyses per se don’t have enough power to unveil the mechanisms involved in disorders.

You are working with fruit fly (Drosophila) models. What do these entail and why are fruit flies beneficial as study objects?

– Fruit flies, despite the morphological differences to humans, share about 75% of their genes, the most meaningful part of the genome, with us. The neural system in Drosophila shares its building blocks and responds to light, darkness, hunger and stress. Also, the neurotransmitters, substances responsible for the communication between nerve cells, such as dopamine, acetylcholine, glutamate and gamma-aminobutyric acid (GABA), are largely the same. Even hormones, such as insulin or steroid hormones that lead to the transition from childhood into adulthood are the same. Molecular signaling pathways can also be highly conserved. Everything tends to be simpler in Drosophila though, with one gene in Drosophila often representing a family of genes in humans. Flies possess fewer neurons, about 250 000, compared to our 86 billion. This can be an advantage when you look at exploring such a complex system as the nervous system, and looking for proofs of principles. When using Drosophila to study a certain gene that causes a disease in humans, we must start by considering how similar both molecules are, and what the likelihood of their function being preserved is. This also brings some limitations to the genes that you can actually study using this organism.
What kind of knowledge can research in this field contribute with?

– Drosophila melanogaster has been developed for more than a century as a subject for genetic studies. There already exist enormous toolboxes and resources that are available to everyone. There are, for example, collections of thousands of flies that allow us to manipulate any genes of interest in a way we like to, within a matter of only two to three weeks. The fly has a quick life cycle, is very cheap to maintain and doesn’t “come with ethical constraints”, which makes it an extremely powerful “tool” to study the impact of a certain gene on a molecular pathway or behaviour. In this way we can study “genes at work” and learn what they are doing.

– Using flies to study behaviour is a more recent field. It opens up possibilities for understanding different simpler aspects of neuropsychiatric disorders, called endophenotypes, and try to link these to elementary neuronal circuits. Our lab has gathered experience in using assays of fly behaviour such as motor activity, difference in circadian rhythm, learning paradigms, and even social interaction.

– In my project I am studying behaviours that can be relevant for hyperactivity and autism. Previous studies with genes related to ADHD in our lab have found a pattern of night hyperactivity in affected animals, with a decrease in total amount of sleep. Habituation has been described as a form of learning highly conserved across species, and defects in this behaviour have been linked to intellectual disability genes. I will use these tests and a social behaviour assay, and try to understand if these can somehow be linked, or else differentially affected in several genetic conditions. We expect this to allow us to relate genes with affected neuronal pathways, and try to restore normal behaviour by genetic and/or pharmacological manipulation of adult flies.

– The main idea is that we have specific techniques to link genetics, behavior, neurobiology and pharmacological testing.

What are the potential practical implications of research on this topic, i.e., how it is relevant and useful in practice?

– This type of approach is useful first of all because it increases knowledge on how the brain works at the molecular level and second because it allows specific drug testing.
– I would like to get a deeper understanding of what the common core mechanisms of autism and ADHD are. Maybe some of these, such as sleep defects, are also common to other neuropsychiatric disorders. By studying molecular basis of behaviour in the fly we would like to propose new biomarkers for brain activity in patients that could maybe be linked to their genetic background.

– In Drosophila we have the possibility to make high throughput drug testing and link treatment to output behaviour. Studying flies can, for example, hopefully help us to find drugs that are effective for certain subsets of intellectual disabilities. These have often been overlooked as they were considered to result from irreparable brain damage. Growing evidence however points towards a partially reversible situation in some cases. Identifying these on flies could put us in a better position to test treatments in selected patients with intellectual disability. This is already being done in some projects in our lab, in collaboration with clinical departments, for some genetic disorders.

Nanna Gillberg

Researcher’s Corner was launched on the Gillberg Neuropsychiatry Centre’s (GNC) website in January 2013. Researcher’s Corner is a series of interviews with researchers linked to the GNC. It features researchers from all GNC’s affiliates around the world with new interviews being launched on a monthly basis. The invited researchers are given the opportunity to describe their current research, make a survey of a field of research or immerse themselves in a topic of their interest. Researcher’s Corner aims to present cutting-edge research within the field of developmental neurology and neuropsychiatry in a straightforward way. The interview series covers a broad spectrum of neuropsychiatric diagnoses from a range of relevant themes – assessment and evaluation work, diagnosing, interventions, school environment and school difficulties as well as collaboration between authorities working to provide support, achieve equal conditions and ensure full societal participation for all members of society.