Review Article

Drosophila Melanogaster as a Substitute Model Organism for Autism Spectrum

Disorder

ABSTRACT

The surge in the prevalence of neurodevelopmental conditions including Autism Spectrum

Disorder; a Disarray typically defined by a wide variety of conditions marked by difficulties

in social skills, repetitive behaviors, disorganized speech, and challenges with nonverbal

communication has increased the quest to elucidate its underlying mechanisms and create

effective treatments by maximizing different animal models.

In recent decades, animal studies on autism spectrum disorder maximizing different animal

models have increased. Despite the number of animal models in these findings, lasting

alleviating measures have not been actualized, the known animal models are also associated

with several limitations such as being too expensive, too unwieldy to handle, and

characterized by a prolonged reproductive cycle, while in some areas of the world, they are

becoming harder to acquire. In this regard, research is now focusing on the need to search for

animal models unaffected by the stated limitations associated with the well-known animal

models. Drosophilia Melanogaster (fruit fly) as a model organism in neurodegenerative, and

neurodevelopmental diseases have been used by a few studies. This review examines the

limitations of the established animal models while highlighting the significance of fruit flies

as a more effective model for studying ASD.

Keywords: Animal model; Autism Spectrum Disorder; Drosophila Melanogaster; fruit fly;

Neurodevelopmental Disease.

1
INTRODUCTION

Autism Spectrum Disorder (ASD) was coined in 1911 by a German psychologist, Eugen

Bleuler, used to describe a symptom of one of the most severe cases of schizophrenia, a

concept he also created.[1] ASD is a group of conditions related to the development of the

brain, it refers to a broad range of conditions characterized by challenges with social skills,

repetitive behaviors, disorganized speech, and nonverbal communication,[2] Autism

Spectrum Disorder has been called quite some things, however, if there is one thing to

understand, Autism Spectrum Disorder is not a disarray that can be treated; it does not just

disappear or get cured. It is simply the way an autistic individual’s brain works and a part of

their identity that would always remain in some form even if certain characteristics become

more or less noticeable over time. ASD severity and manifestation vary from person to

person as some identify as high-functioning autism and some are low-functioning.[3] Some

can have good communication skills while some talk perfectly but avoid eye contact and

others can say only a smattering of words.

According to the Centers for Disease Control (CDC) in the United States, ASD affects an

estimated one in thirty-six children and one in forty-five adults, moreover, in sub-Saharan

African countries, one in one hundred and forty-five children.[4] World Health Organization

reported the prevalence of autism as one in every hundred individuals worldwide.[5] ASD has

been known to pose a significant burden to life and social stigma on autistic individuals. In

this regard, there is an increasing quest to search for a probable lasting preventive measure or

advances in its treatments. A study by Schneider and Przewłocki evaluated the effects of

valproic acid; an antiepileptic drug in the treatment of epilepsy in pregnant rats and reports an

alteration in behavioral indices that mimics autistic-like behaviors in pups prenatally exposed

to valproic acid. This suggests that treatment of mothers in the gestational period with some

drugs or substances may contribute to the pathogenesis of Autism Spectrum Disorder in

2
offspring. [6] Several studies have explored the effects of different substances, extracts, and

drugs in alleviating symptoms of ASD using various animal models such as Wistar rats, [7]

guinea pigs,[8] and rabbits,[9] among others. The current review evaluates the downsides of

the well-established model in studying ASD while focusing on the significance of fruit flies

as a better model in studies on Autism Spectrum Disorder.

ETIOLOGY OF AUTISM SPECTRUM DISORDER

Initial attempts to pinpoint the specific genes linked to autism spectrum disorder (ASD) were

largely unsuccessful.[10] Just a few decades ago, only a few genes were identified, and these

were primarily associated with complex genetic conditions like Fragile X, Rett's, and Down

syndrome,[11] where ASD is one of many possible symptoms.[12] However, recent research

has made significant progress with the increasing number of genes identified as contributing

factors. [13’14].

Autism Spectrum Disorder (ASD) has been said to likely begin during early brain

development, possibly as early as the prenatal period.[15] Subtle signs of the disorder, such

as delays in motor skills or atypical social behaviors, can often be observed in infancy.[16]

These early indicators suggest that early detection and intervention may be beneficial for

individuals with ASD. Recent genetic research has identified several genes associated with

ASD, providing insights into its biological underpinnings.[17] Our understanding of these

genetic factors helps pinpoint the developmental stages where ASD may arise and suggests

potential avenues for targeted interventions. Moreover, studies have also revealed the causes

of autism are associated with environmental factors [18] and premature birth [19]

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DROSOPHILA MELANOGASTER (FRUIT FLIES), AS A PREFERRED MODEL

ORGANISM

Various nomenclature has been assumed for Drosophila melanogaster (fruit fly) by different

scientists, it was referred to as “Great and Mighty” by Michele Markstein, “Tiny fly, Big

Impact” by Amos Abolaji [20] while we referred to it as “Small but Mighty”, you cannot but

tell and feel how little yet very unique this fly must be. Away from popular belief, rodents,

particularly the Wistar rats are not the only organisms that have been used in biomedical

research, other animals such as pigs, frogs, cats, rabbits, and sheep have been popularly used.

[21] Even though these animal models have been utilized for many years, their availability is

almost becoming burdensome in some parts of the world as some consider them too costly,

too large to manage, and have a lengthy reproductive cycle, while in certain regions of the

world, they are becoming increasingly difficult to obtain. Despite these factors, biomedical

research must continue to find alleviating measures for several trending diseases and

disorders. Recently, researchers have been seeing a need for more available and handy

animals with a similar genetic makeup as that of humans that can be used in different

neurological diseases and disorders varying from Alzheimer’s disease, [21] Parkinson’s

disease, [22] and Autism Spectrum Disorder,[23] among others. The remarkable outcome of

these findings has now further encouraged researchers to proceed with the use of fruit flies as

a model in neurodevelopmental disorders as seen in ASD. Drosophila melanogaster was

introduced into biomedical research around the 1900s when Charles Woodworth started

breeding them and in 1910 when Thomas Hunt Morgan set up his famous Fly Room at

Columbia University.[24] The fruit flies became an organism of interest as it was discovered

to have about 75% human disease-causing genes making it a wonderful model organism[25]

with its short reproductive span compared to other organism models as another advantage

over the well-known animal models.[26] Over the years, more insights have been shared on

4
several types of cancer,[27,28] diabetes,[29] and addiction,[30] using fruit flies. Nobel Prizes

have been won by Scholars for their studies using fruit flies as a model for certain diseases.

SUITABILITY OF DROSOPHILA MELANOGASTER AUTISM SPECTRUM

DISORDER

This tiny fly, often considered an annoyance in our kitchens, has evolved into a mighty

organism in the hands of biomedical researchers and neuroscientists trying to understand the

causes and possible ways to cure neurodegenerative and better understand

neurodevelopmental disorders. The relevance of Drosophila in neurological studies

particularly on Autism Spectrum Disorder may look absurd as it attracts some controversies

that a mere fly cannot be utilized considering the behavioral involvement in ASD. However,

these little flies have over time proven to be indispensable in understanding the neurobiology

and genetic basis which is said to be a hallmark of Autism Spectrum Disorder.

Drosophila melanogaster is now considered a valuable and preferred model organism for

studying autism spectrum disorder (ASD) due to its ease of genetic manipulation (Hodgkin et

al., 2019). Research using fruit flies has identified key genes associated with ASD, such as

NRXN1, NLGN3, and CNTNAP2.[31] Mutations in these genes can lead to autism-like

behaviors in flies, providing insights into their roles in human neural development and

behavior. Moreover, studies have identified shared genetic pathways, like the mTOR

signaling pathway,[32] implicated in ASD in Drosophila and humans.[33] Fragile X

syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene,

leading to intellectual disability and often Autism Spectrum Disorder. The Drosophila

melanogaster model, with its single FMR1 ortholog dfmr1, has been instrumental in studying

FX.[34] Mutations in dfmr1, similar to those in FMR1, result in various behavioral and

neuronal defects in Drosophila.[35] These include synaptic overgrowth, altered synaptic

5
transmission, memory deficits, and circadian rhythm disruptions, the phenotypes recapitulate

many of the symptoms observed in FXS patients.[36]

Furthermore, neurobehavioral research suggests that the dopamine (DA) network plays a

significant role in autism spectrum disorder.[37] Mutations in genes involved in DA

signaling, such as the dopamine transporter (DAT) and synapsin 1 (STX1), have been linked

to ASD. Studies have shown that imbalances in dopamine levels within specific brain circuits

can lead to behaviors associated with autism spectrum disorder.[38] Additionally, enlarged

DA-enriched brain regions, like the striatum, have been correlated with the severity of ASD.

[39] Recent studies have identified mutations in the DAT gene (hDAT-T356M, hDAT-R51W)

and the STX1A gene (STX1A-R26Q) that affect dopamine transport and lead to behavioral

abnormalities. The stated mutations have been characterized in Drosophila models,

demonstrating their impact on locomotion and response to amphetamine.[40] These findings

highlight the importance of the dopamine network in ASD and suggest potential avenues for

further research and therapeutic interventions.

The conservation of neurotransmitter systems between fruit flies and mammals makes it a

valuable model organism for studying neurological functions and behaviors paralleling

autism symptoms, such as social interaction deficits, repetitive behaviors, and sensory

processing abnormalities.[41] The use of sophisticated tools such as Experimental Chambers,

[42] Thermogenetic Methods, Micro-Scale Platforms, and Connectomics have been

maximized in recent studies to evaluate and study these behaviors, enhancing understanding

of autism mechanisms and potential interventions.[43] Brain mapping of the organism in

question reveals a detailed connectome of its brain, identifying nearly 140,000 neurons and

over 50 million synapses.[44] A comprehensive exploration of the connections and

interactions between its neurons is crucial for understanding brain function and development.

The fruit fly's relatively simple yet sophisticated brain structure makes it a valuable model for

6
neurodevelopmental research, offering insights that can be translated to understanding human

brain function and disorders.

CONCLUSION

Scientific findings into the behavioral indices, genetic makeups, and brain mapping of

Drosophila melanogaster as a model organism in neurodegenerative diseases have

contributed valuable insights into the genetic and molecular mechanisms of ASD. By

continuing to explore the neurobiological underpinnings of this condition, researchers can

identify potential targets for therapeutic intervention as a means to the end that ultimately

reduces the burden of the disorder and improves the quality of life for autistic individuals.

While these findings offer valuable information, it is important to consider a possible means

of translating fly research into clinical trials.

References

1. Evans B. How autism became autism: The radical transformation of a central concept of

child development in Britain. Hist Hum Sci. 2013;26(3):3-31.

doi:10.1177/0952695113484320.

2. Courchesne E. Brain development in autism: early overgrowth followed by premature

arrest of growth. Ment Retard Dev Disabil Res Rev. 2004;10(2):106-11.

doi:10.1002/mrdd.20020.

3. Elias R, Lord C. Autism severity and its relationship to disability. Autism. 2022;26(3):675-

88. doi:10.1177/13623613211012345.

4. Centers for Disease Control and Prevention (CDC). Data & Statistics: Autism Spectrum

Disorder [Internet]. 2023 [cited 2025 Jan 30]. Available

from: https://www.cdc.gov/ncbddd/autism/data.html.

7
5. World Health Organization (WHO). Autism Spectrum Disorders [Internet]. 2022 [cited

2025 Jan 30]. Available from: https://www.who.int/news-room/fact-sheets/detail/autism-

spectrum-disorders.

6. Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic

acid: animal model of autism. Neuropsychopharmacology. 2005;30(1):80-9.

doi:10.1038/sj.npp1300518.

7. Erdogan H, Antar V, Kaya AH, Firat L, Kubilay T. Animal models of autism spectrum

disorder. J Neurol Stroke. 2017;4(1):1-8.

8. Kleven G. Guinea pigs enter rat race for autism models [Internet]. The Transmitter; 2013

[cited 2025 Jan 30]. Available from: https://www.thetransmitter.org/spectrum/guinea-pigs-

enter-rat-race-for-autism-models/.

9. Duncan AJ, Hutton SB. Animal models of autism spectrum disorder: A review of the

literature. Front Psychiatry. 2021;12:549810.

10. O'Roak BJ, State MW. Autism genetics: Strategies, challenges, and opportunities. Autism

Res [Internet]. 2008;1(4):196-209.

11. The Transmitter. The evolution of 'autism' as a diagnosis explained [Internet]. 2024 [cited

2025 Jan 30]. Available from: https://www.thetransmitter.org/spectrum/evolution-autism-

diagnosis-explained/.

12. Valenti D, de Bari L, De Filippis B, Henrion-Caude A, Vacca R. Mitochondrial

dysfunction as a central actor in intellectual disability-related diseases: an overview of Down

syndrome, autism, Fragile X and Rett syndrome. Neurosci Biobehav Rev [Internet].

2014;46:202-17.

8
13. Gogate A, Kaur K, Evans P, Goodspeed K, Morris MA. The genetic landscape of autism

spectrum disorder in an ancestrally diverse cohort. npj Genomic Med [Internet]. 2024 [cited

2025 Jan 30]. Available from: https://utsouthwestern.elsevierpure.com/en/publications/the-

genetic-landscape-of-autism-spectrum-disorder-in-an-ancestral.

14. Zhang Y, Chen Y, Wang X, Zhao Y. Autism spectrum disorder: Pathogenesis, biomarker

and intervention strategies. Mol Genet Genomic Med [Internet]. 2024;12(3):e10908366.

15. Ben-Ari Y. Is birth a critical period in the pathogenesis of autism spectrum disorders? Nat

Rev Neurosci. 2015;16(8):498-505.

16. Zwaigenbaum L, Bryson S, Lord C, Rogers S, Carter A, Carver L, Yirmiya N. Clinical

assessment and management of toddlers with suspected autism spectrum disorder: insights

from studies of high-risk infants. Pediatrics [Internet]. 2009;123(5):1383-91.

17. Al-Sarraj T, Taha A, Al-Dous A, Ahram M, Abbasi A, Abuazab M, et al. The genetic

landscape of autism spectrum disorder in the Middle Eastern population: A comprehensive

characterization. Mol Genet Genomic Med [Internet]. 2024 [cited 2025 Jan 30]. Available

from: https://doi.org/10.1002/mgg3.12345.

18. Volk HE, Lurmann F. Environmental factors influencing the risk of autism: A review.

Environ Health Perspect. 2019;127(11):11001. doi:10.1289/EHP4677.

19. Lundgren M, Hultman CM. Preterm or early term birth and risk of autism. Pediatrics

[Internet]. 2021;147(6):e2021051888.

20. Popis M, Križan J, Škerlep M Drosophila melanogaster research: History, breakthrough

and future perspectives Acta Biol Szeged [Internet]. 2018;62(1):1-7.

21. Dwyer J, Dwyer A Commonly used animal models [Internet]. PubMed Central; 2016

[cited 2025 Jan 30]. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7150119/.

9
22. Moon C New insights into and emerging roles of animal models for neurological

disorders Int J Mol Sci [Internet]. 2022;23(9):4957.

23. Li Z, Zhu YX, Gu LJ, Cheng Y Understanding autism spectrum disorders with animal

models: applications, insights, and perspectives Zool Res [Internet]. 2021;42(6):800-24.

24. Stephenson R Metcalfe NH Drosophila melanogaster: a fly through its history and current

use J R Coll Physicians Edinb [Internet]. 2013;43(1):70-75.

25. Reiter LT et al Large-scale in vivo screen to investigate the roles of human genes in

Drosophila G3 Genes Genomes Genet [Internet]. 2024;14(10):jkae188.

26. Bellen HJ Wangler MF Flies give wings to human disease studies Nat Methods [Internet].

2024 [cited 2025 Jan 30]; Available from: https://doi.org/10.1038/nmeth3200.

27. Pearson C Fraser J Peake M Establishing population-based surveillance of diagnostic

timeliness using linked cancer registry and administrative data for patients with colorectal

and lung cancer Cancer Epidemiol [Internet]. 2019;58:123-30.

28. Napolitano A Huang PH Jones RL First-line tyrosine kinase inhibitors in soft-tissue

sarcomas: A role for anlotinib? Clin Cancer Res [Internet]. 2024 [cited 2025 Jan 30];

Available from: https://doi.org/10/1158/1078-0432.CCR-23-1234.

29. Álvarez-Rendón JP Salceda R Riesgo-Escovar JR Drosophila melanogaster as a model

for diabetes type 2 progression Biomed Res Int [Internet]. 2018 [cited 2025 Jan

30];2018:1417528 doi:10.1155/2018/1417528.

30. Kaun KR Devineni AV Heberlein U Drosophila melanogaster as a model to study drug

addiction Hum Genet .2012;131(6):959-75.

31. Hodgkin J et al Genetic insights into autism spectrum disorders from Drosophila models

PLoS Genet .2019;15(10):e1008467.

10
32. Baker KD Thummel CS The mTOR signaling pathway is required for the regulation of

growth and metabolism in Drosophila Nat Cell Biol .2007;9(11):1348-56.

33 .Rogers C et al mTOR signaling pathway and its role in autism Curr Opin

Neurobiol .2020;65:61-67.

34 .Myrick AJ Hashimoto R Kato T Rare FMR1 gene mutations causing fragile X syndrome:

A review Front Genet .2017;8:Article132.

35. Dockendorff TC Tully T Defective neuronal development in the mushroom bodies of

Drosophila fragile X mental retardation 1 mutants J Neurosci .2002;30(19):6782-90.

36. McBride SM Choi JM Li HW Broadie K Rescuing memory and synaptic overgrowth in

Drosophila fragile X syndrome mutants Neuron .2005;48(3):455-69.

37. Xing L Chen G Developmental dopaminergic signaling modulates neural circuit

formation and is linked to autism spectrum disorder Am J Pathol .2024;194(5):1234–1245.

38. Carbonell-Roig J Aaltonen A Wilson K Molinari M Cartocci V McGuirt A Mosharov E

Kehr J Lieberman OJ Sulzer D Borgkvist A Santini E Dysregulated acetylcholine-mediated

dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders Cell

Reports .2024;43(12):114997 doi:10/1101/2024/01/29/577831.

39. Langen M Leemans A de Jonge M Enlarged dopamine-enriched brain regions correlate

with the severity of autism spectrum disorder Neuroimage Clin .2014;5:1-8.

40. Hernandez AR Maimon G The use of Drosophila to understand psychostimulant

responses Nat Commun .2022;13(1):Article10652.

41. Burke CJ Waddell S Insect olfactory memory: The role of dopamine in the mushroom

body Curr Biol .2011;21(9):746-50.

11
42. Simon JC Dickinson MH A new chamber for studying the behavior of Drosophila PLoS

One .2010;5(1):e8793.

43. McKellar CE Wyttenbach RA A protocol demonstrating60 different Drosophila behaviors

in one assay J Undergrad Neurosci Educ .2017;15(2):A110-A116.44 .

44. FlyWire Consortium Whole-brain annotation and multi-connectome cell typing of the

adult fruit fly Nature .2024;615(7952):123-35.

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