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Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder

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Abstract

Background

The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders.

Methods

We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5′ flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case–control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated.

Results

A significantly higher occurrence of rs1800955 “T/TT” was observed in the probands. ASD traits were affected by rs1800955 “T” and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 “6R” and rs27072 “CC” and DRD4 rs4646984 higher repeat allele and rs1800955 “T”.

Conclusion

This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis.

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Data availability

Data generated for the study are presented in tabular format as Tables, figures, and Additional files. Further details on data will be available from the corresponding author on reasonable request.

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Association; 2013.

    Book  Google Scholar 

  2. Maenner MJ, Shaw KA, Baio J, Washington A, Patrick M, DiRienzo M, et al. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill Summ. 2020;69:1–12.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Poovathinal SA, Anitha A, Thomas R, Kaniamattam M, Melempatt N, Anilkumar A, et al. Prevalence of autism spectrum disorders in a semiurban community in south India. Ann Epidemiol. 2016;26:663-5.e8.

    Article  PubMed  Google Scholar 

  4. Rudra A, Belmonte MK, Soni PK, Banerjee S, Mukerji S, Chakrabarti B. Prevalence of autism spectrum disorder and autistic symptoms in a school-based cohort of children in Kolkata, India. Autism Res. 2017;10:1597–605.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Casanova MF, Frye RE, Gillberg C, Casanova EL. Editorial: co-morbidity and autism spectrum disorder. Front Psychiatry. 2020;11:617395.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Money KM, Stanwood GD. Developmental origins of brain disorders: roles for dopamine. Front Cell Neurosci. 2013;7:260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Paval DA. Dopamine hypothesis of autism spectrum disorder. Dev Neurosci. 2017;39:355–60.

    Article  CAS  PubMed  Google Scholar 

  8. Hosenbocus S, Chahal R. A review of executive function deficits and pharmacological management in children and adolescents. J Can Acad Child Adolesc Psychiatry. 2012;21:223–9.

    PubMed  PubMed Central  Google Scholar 

  9. Lewis MH, Tanimura Y, Lee LW, Bodfish JW. Animal models of restricted repetitive behavior in autism. Behav Brain Res. 2007;176:66–74.

    Article  PubMed  Google Scholar 

  10. Langen M, Leemans A, Johnston P, Ecker C, Daly E, Murphy CM, et al. Frontostriatal circuitry and inhibitory control in autism: findings from diffusion tensor imaging tractography. Cortex. 2012;48:183–93.

    Article  PubMed  Google Scholar 

  11. Fuccillo MV. Striatal circuits as a common node for autism pathophysiology. Front Neurosci. 2016;10:27.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kosillo P, Bateup HS. Dopaminergic dysregulation in syndromic autism spectrum disorders: insights from genetic mouse models. Front Neural Circuits. 2021;15:700968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nguyen M, Roth A, Kyzar EJ, Poudel MK, Wong K, Stewart AM, et al. Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD). Neurochem Int. 2014;66:15–26.

    Article  CAS  PubMed  Google Scholar 

  14. DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, et al. Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. J Clin Invest. 2019;129:3407–19.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chao OY, Pathak SS, Zhang H, Dunaway N, Li JS, Mattern C, et al. Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism. Mol Brain. 2020;13:111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kaluzna-Czaplinska J, Socha E, Rynkowski J. Determination of homovanillic acid and vanillylmandelic acid in urine of autistic children by gas chromatography/mass spectrometry. Med Sci Monit. 2010;16:CR445-50.

    CAS  PubMed  Google Scholar 

  17. Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992;34:593–603.

    Article  CAS  PubMed  Google Scholar 

  18. Alsayouf HA, Talo H, Biddappa ML, Qasaymeh M, Qasem S, De Los RE. Pharmacological intervention in children with autism spectrum disorder with standard supportive therapies significantly improves core signs and symptoms: a single-center, retrospective case series. Neuropsychiatr Dis Treat. 2020;16:2779–94.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28:1400–11.

    Article  CAS  PubMed  Google Scholar 

  20. Hirsch LE, Pringsheim T. Aripiprazole for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2016;2016:CD009043.

    PubMed  PubMed Central  Google Scholar 

  21. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996;379:606–12.

    Article  CAS  PubMed  Google Scholar 

  22. Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol. 2012;45:605–20.

    Article  CAS  PubMed  Google Scholar 

  23. Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ. Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology. 1996;15:17–29.

    Article  CAS  PubMed  Google Scholar 

  24. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001–10.

    Article  CAS  PubMed  Google Scholar 

  25. Klein M, van Donkelaar M, Verhoef E, Franke B. Imaging genetics in neurodevelopmental psychopathology. Am J Med Genet B Neuropsychiatr Genet. 2017;174:485–537.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wehmuth M, Antoniuk A, Silva KB, Raskinb S, Christoff A, Frigeri HR. Dopamine DRD4 gene polymorphism as a risk factor for epilepsy in autism spectrum disorder. J Biol Med. 2020;4:012–7.

    Google Scholar 

  27. Gadow KD, Devincent CJ, Olvet DM, Pisarevskaya V, Hatchwell E. Association of DRD4 polymorphism with severity of oppositional defiant disorder, separation anxiety disorder and repetitive behaviors in children with autism spectrum disorder. Eur J Neurosci. 2010;32:1058–65.

    Article  PubMed  Google Scholar 

  28. Reiersen AM, Todorov AA. Association between DRD4 genotype and autistic symptoms in DSM-IV ADHD. J Can Acad Child Adolesc Psychiatr. 2011;20:15–21.

    Google Scholar 

  29. Maitra S, Chatterjee M, Sinha S, Mukhopadhyay K. Dopaminergic gene analysis indicates influence of inattention but not IQ in executive dysfunction of Indian ADHD probands. J Neurogenet. 2019;33:209–17.

    Article  CAS  PubMed  Google Scholar 

  30. Xu FL, Wu X, Zhang JJ, Wang BJ, Yao J. A meta-analysis of data associating DRD4 gene polymorphisms with schizophrenia. Neuropsychiatr Dis Treat. 2018;14:153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschläger L, et al. Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatr. 2011;12:104–8.

    Article  Google Scholar 

  32. Saha S, Chatterjee M, Shom S, Sinha S, Mukhopadhyay K. Functional SLC6A3 polymorphisms differentially affect autism spectrum disorder severity: a study on Indian subjects. Metab Brain Dis. 2022;37:397–410.

    Article  CAS  PubMed  Google Scholar 

  33. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000.

    Google Scholar 

  34. Schopler E, Van Bourgondien ME, Wellman GJ, Love SR. Childhood autism rating scale. 2nd ed. Los Angeles: Western Psychological Services; 2010.

    Google Scholar 

  35. D’Souza UM, Russ C, Tahir E, Mill J, McGuffin P, Asherson PJ, et al. Functional effects of a tandem duplication polymorphism in the 5′ flanking region of the DRD4 gene. Biol Psychiatr. 2004;56:691–7.

    Article  Google Scholar 

  36. Okuyama Y, Ishiguro H, Toru M, Arinami T. A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Commun. 1999;258:292–5.

    Article  CAS  PubMed  Google Scholar 

  37. Catalano M, Nobile M, Novelli E, Nothen MM, Smeraldi E. Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biol Psychol. 1993;34:459–64.

    Article  CAS  Google Scholar 

  38. Schoots O, Van Tol HH. The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics J. 2003;3:343–8.

    Article  CAS  PubMed  Google Scholar 

  39. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maitra S, Sarkar K, Ghosh P, Karmakar A, Bhattacharjee A, Sinha S, et al. Potential contribution of dopaminergic gene variants in ADHD core traits and comorbidity: a study on eastern Indian probands. Cell Mol Neurobiol. 2014;34:549–64.

    Article  CAS  PubMed  Google Scholar 

  41. Bhaduri N, Das M, Sinha S, Chattopadhyay A, Gangopadhyay PK, Chaudhuri K, et al. Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population. Am J Med Genet Neuropsychiatr Genet. 2006;141:61–6.

    Article  Google Scholar 

  42. Das M, Das Bhowmik A, Bhaduri N, Sarkar K, Ghosh P, Sinha S, et al. Role of gene-gene/gene-environment interaction in the etiology of eastern Indian ADHD probands. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:577–87.

    Article  CAS  PubMed  Google Scholar 

  43. Xu X, Mill J, Sun B, Chen CK, Huang YS, Wu YY, et al. Association study of promoter polymorphisms at the dopamine transporter gene in attention deficit hyperactivity disorder. BMC Psychiatr. 2009;9:3.

    Article  Google Scholar 

  44. Dudbridge F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered. 2008;66:87–98.

    Article  PubMed  Google Scholar 

  45. Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics. 2003;19:376–82.

    Article  CAS  PubMed  Google Scholar 

  46. Abrahams S, McFie S, Lacerda M, Patricios J, Suter J, September AV, et al. Unravelling the interaction between the DRD2 and DRD4 genes, personality traits and concussion risk. BMJ Open Sport Exerc Med. 2019;5:e000465.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Barkley RA, Smith KM, Fischer M, Navia B. An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40bp VNTR) in hyperactive and normal children followed to adulthood. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:487–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kamal M, Elnady G, Abushady A, Khalil M. Association of dopamine D4 receptor gene variants with autism. Int J Res Med Sci. 2015;3:2658–63.

    Article  Google Scholar 

  49. Emanuele E, Boso M, Cassola F, Broglia D, Bonoldi I, Mancini L, et al. Increased dopamine DRD4 receptor mRNA expression in lymphocytes of musicians and autistic individuals: bridging the music-autism connection. Neuro Endocrinol Lett. 2010;31:122–5.

    PubMed  Google Scholar 

  50. Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschläger L, et al. Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatr. 2011;12(Suppl 1):104–8.

    Article  Google Scholar 

  51. Schalbroeck R, van Velden FHP, de Geus-Oei LF, Yaqub M, van Amelsvoort T, Booij J, et al. Striatal dopamine synthesis capacity in autism spectrum disorder and its relation with social defeat: an [18F]-FDOPA PET/CT study. Transl Psychiatry. 2021;11:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pascucci T, Colamartino M, Fiori E, Sacco R, Coviello A, Ventura R, et al. P-cresol alters brain dopamine metabolism and exacerbates autism-like behaviors in the BTBR mouse. Brain Sci. 2020;10:233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Scott-Van Zeeland AA, Dapretto M, Ghahremani DG, Poldrack RA, Bookheimer SY. Reward processing in autism. Autism Res. 2010;3:53–67.

    PubMed  PubMed Central  Google Scholar 

  54. Ernst M, Zametkin AJ, Matochik JA, Pascualvaca Cohen RM. Low medial prefrontal dopaminergic activity in autistic children. Lancet. 1997;350:638.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are thankful to the study participants for volunteering in the study. In addition, we are grateful to Dr. C Saha for his help during the statistical analysis.

Funding

This work was partially supported by the CSR fund (2021–2022) received from the Ganapati Sugar Industries Ltd, India. No other ad hoc financial support was received.

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Authors and Affiliations

  1. Manovikas Biomedical Research and Diagnostic Centre, Manovikas Kendra, 482 Madudah, Plot I-24, Sector-J, E.M. Bypass, Kolkata, West Bengal, 700107, India

    Sharmistha Saha, Mahasweta Chatterjee, Nilanjana Dutta, Swagata Sinha & Kanchan Mukhopadhyay

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  1. Sharmistha Saha
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  2. Mahasweta Chatterjee
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  3. Nilanjana Dutta
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  4. Swagata Sinha
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Contributions

SSh: resource, data curation, investigation, formal analysis, writing–original draft. CM: investigation, formal analysis. DN: investigation. SSw: investigation. MK: conceptualization, investigation, writing—review and editing. All the authors approved the final manuscript.

Corresponding author

Correspondence to Kanchan Mukhopadhyay.

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No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

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All the procedures involving human participants were performed following the ethical standards of the institutional research committee, which follows the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol was approved by the Human Ethical Committee of the institute (PR-005-19). Written informed consent to participate in the study has been obtained from the participants (or their parent or legal guardian in the case of children under 16).

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Saha, S., Chatterjee, M., Dutta, N. et al. Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder. World J Pediatr 19, 770–781 (2023). https://doi.org/10.1007/s12519-023-00702-0

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