Skip to main content
SpringerLink
Log in

Impact of Auditory Integration Therapy (AIT) on the Plasma Levels of Human Glial Cell Line–Derived Neurotrophic Factor (GDNF) in Autism Spectrum Disorder

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Neurotrophic factors, including the glial cell line–derived neurotrophic factor (GDNF), are of importance for synaptic plasticity regulation, intended as the synapses’ ability to strengthen or weaken their responses to differences in neuronal activity. Such plasticity is essential for sensory processing, which has been shown to be impaired in autism spectrum disorder (ASD). This study is the first to investigate the impact of auditory integration therapy (AIT) of sensory processing abnormalities in autism on plasma GDNF levels. Fifteen ASD children, aged between 5 and 12 years, were enrolled and underwent the present research study. AIT was performed throughout 10 days with a 30-min session twice a day. Before and after AIT, Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma GDNF levels were assayed by an EIA test. A substantial decline in autistic behavior was observed after AIT in the scaling parameters used. Median plasma GDNF level was 52.142 pg/ml before AIT. This level greatly increased immediately after AIT to 242.05 pg/ml (P < 0.001). The levels were depressed to 154.00 pg/ml and 125.594 pg/ml 1 month and 3 months later, respectively, but they were still significantly higher compared with the levels before the treatment (P = 0.001, P = 0.01, respectively). There was an improvement in the measures of autism severity as an effect of AIT which induced the up-regulation of GDNF in plasma. Further research, on a large scale, is needed to evaluate if the cognitive improvement of ASD children after AIT is related or not connected to the up-regulation of GDNF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ASD:

autism spectrum disorder

AIT:

auditory integration training

CARS:

Childhood Autism Rating Scale

dBA:

decibel

GDNF:

glial cell line–derived neurotrophic factor

(5-HT):

serotonergic

OSHA:

Occupational Safety and Health Act

SSP:

Short Sensory Profile

SRS:

Social Responsiveness Scale

References

  • Al-Ayadhi LY, Al-Drees A, Al-Arfaj AM (2013) Effectiveness of auditory integration therapy in autism spectrum disorders — prospective study. Autism Insights 5:13–20. https://doi.org/10.4137/AUI.S11463

    Article  Google Scholar 

  • Allen KM, Purves-Tyson TD, Fung SJ, Shannon Weickert C (2015) The effect of adolescent testosterone on hippocampal BDNF and TrkB mRNA expression: relationship with cell proliferation. BMC Neurosci 16:4. https://doi.org/10.1186/s12868-015-0142-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • American Psychiatric Association (ed) (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington

    Google Scholar 

  • Bakshi A, Shimizu S, Keck CA, Cho S, LeBold DG, Morales D, Arenas E, Snyder EY, Watson DJ, McIntosh TK (2006) Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury. Eur J Neurosci 23:2119–2134

    Article  PubMed  Google Scholar 

  • Baranek GT (2002) Efficacy of sensory and motor interventions for children with autism. J Autism Dev Disord 32:397–422

    Article  PubMed  Google Scholar 

  • Baranek GT, Foster LG, Berkson G (1997a) Sensory defensiveness in persons with developmental disabilities. Occup Ther J Res 17:173–185

    Article  Google Scholar 

  • Baranek GT, Foster LG, Berkson G (1997b) Tactile defensiveness and stereotyped behaviors. Am J Occup Ther 51:91–95

    Article  CAS  PubMed  Google Scholar 

  • Berard G (1993) Hearing equals behavior. Keats Publishing, New Canaan

    Google Scholar 

  • Bourgeron T (2015) From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 16:551–563

    Article  CAS  PubMed  Google Scholar 

  • Chung L, Bey AL, Jiang YH (2012) Synaptic plasticity in mouse models of autism spectrum disorders. Korean J Physiol Pharmacol 16:369–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Committee on Children with Disabilities (1998) Auditory integration training and facilitated communication for autism. Pediatrics 102:431–433. https://doi.org/10.1542/peds.102.2.431

    Article  Google Scholar 

  • Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W (2003) Validation of a brief quantitative measure of autistic traits: comparison of the Social Responsiveness Scale with the autism diagnostic interview-revised. J Autism Dev Disord 33:427–433

    Article  PubMed  Google Scholar 

  • Constantino JN, Gruber CP (2007) Social Responsiveness Scale (SRS). Western Psychological Services, Los Angeles

    Google Scholar 

  • Dawson G, Osterling J, Meltzoff A, Kuhl P (2000) Case study of the development of an infant with autism from birth to 2 years of age. J Appl Dev Psychol 21:299–313

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Liberto V, Mudò G, Belluardo N (2011) mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum. Neuropharmacology 61:638–645. https://doi.org/10.1016/j.neuropharm.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  • Dunn W (1999) The sensory profile: examiner’s manual. The psychological corporation, San Antonio

    Google Scholar 

  • Dursun OB (2014) The relationship between vitamin D, autistic spectrum disorders, and cognitive development: do glial cell line-derived neurotrophic factor and nerve growth factor play a role in this relationship? Int J Dev Disabil 61:222–230. https://doi.org/10.1179/2047387714Y.0000000054

    Article  Google Scholar 

  • El-Ansary A, Al-Ayadhi L (2012) Neuroinflammation in autism spectrum disorders. J Neuroinflammation 9(265). https://doi.org/10.1186/1742-2094-9-265

  • El-Ansary A, Hassan WM, Qasem H, Das UN (2016) Identification of biomarkers of impaired sensory profiles among autistic patients. PLoS One 11:e0164153. https://doi.org/10.1371/journal.pone.0164153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farrand AQ, Gregory RA, Scofield MD, Helke KL, Boger HA (2015) Effects of aging on glutamate neurotransmission in the substantia nigra of Gdnf heterozygous mice. Neurobiol Aging 36:1569–1576

    Article  CAS  PubMed  Google Scholar 

  • Ghanbari S, Amin Rezaei A (2016) The relationship between sensory-processing disorders and sleep disturbances in school-aged autistic children in Shiraz, 2015. Jundishapur J Chronic Dis Care 5:e32337. https://doi.org/10.17795/jjcdc-32337

    Article  Google Scholar 

  • Goodman KM, Kjaer S, Beuron F, Knowles PP, Nawrotek A, Burns EM, Purkiss AG, George R, Santoro M, Morris EP, McDonald NQ (2014) RET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Rep 8:1894–1904

    Article  CAS  PubMed  Google Scholar 

  • Hao F, Yang C, Chen SS, Wang YY, Zhou W, Hao Q, Lu T, Hoffer B, Zhao LR, Duan WM, Xu QY (2017) Long-term protective effects of AAV9 mesencephalic astrocyte derived neurotrophic factor gene transfer in parkinsonian rats. Exp Neurol 291:120–133

    Article  CAS  PubMed  Google Scholar 

  • Hibi Y, Nitta A, Nabeshima T, Yamada K (2009) Possible relation of BDNF and GDNF to neuropsychiatric disorders. Japan J Psychopharmacol 29:85–89

    CAS  Google Scholar 

  • Israelyan N, Margolis KG (2019) Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. Pharmacol Res 140:115–120. https://doi.org/. https://doi.org/10.1016/j.phrs.2018.12.023

    Article  PubMed  PubMed Central  Google Scholar 

  • Kabra A, Sharma R, Kabra R, Baghel US (2018) Emerging and alternative therapies for Parkinson disease: an updated review. Curr Pharm Des 24:2573–2582

    Article  CAS  PubMed  Google Scholar 

  • Kientz MA, Dunn W (1997) A comparison of the performance of children with and without autism on the Sensory Profile. Am J Occup Ther 51:530–537

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa H, Hayashi T, Mitsumoto Y, Koga N, Itoyama Y, Abe K (1998) Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 29:1417–1422

    Article  CAS  PubMed  Google Scholar 

  • Kosuge Y, Sekikawa-Nishida K, Negi H, Ishige K, Ito Y (2009) Characterization of chronic glutamate-mediated motor neuron toxicity in organotypic spinal cord culture prepared from ALS model mice. Neurosci Lett 454:165–169. https://doi.org/. https://doi.org/10.1016/j.neulet.2009.03.017

    Article  CAS  PubMed  Google Scholar 

  • Koyama Y, Egawa H, Osakada M, Baba A, Matsuda T (2004) Increase by FK960, a novel cognitive enhancer, in glial cell line-derived neurotrophic factor production in cultured rat astrocytes. Biochem Pharmacol 68:275–282

    Article  CAS  PubMed  Google Scholar 

  • Kramer ER, Liss B (2015) GDNF-ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease. FEBS Lett 589:3760–3772

    Article  CAS  PubMed  Google Scholar 

  • Kronenberg J, Merkel L, Heckers S, Gudi V, Schwab HM, Stangel M (2019) Investigation of neuregulin-1 and glial cell-derived neurotrophic factor in rodent astrocytes and microglia. J Mol Neurosci 67:484–493. https://doi.org/10.1007/s12031-019-1258-8

    Article  CAS  PubMed  Google Scholar 

  • Lee SM, Kim BK, Kim TW, Ji ES, Choi HH (2016) Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups. J Exerc Rehabil 12:148–155

    Article  PubMed  PubMed Central  Google Scholar 

  • Margolis KG (2017) A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure. J Chem Neuroanat 83-84:36–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Cengotitabengoa M, MacDowell KS, Alberich S, Diaz FJ, Garcia- Nickl-Jockschat T, Michel TM (2011) The role of neurotrophic factors in autism. Mol Psychiatry 16:478–490

    Article  CAS  Google Scholar 

  • Mostafa GA, Al-Ayadhi LY (2011) A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children. J Neuroinflammation 8:71. https://doi.org/10.1186/1742-2094-8-71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller CL, Anacker AMJ, Veenstra-VanderWeele J (2016) The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 321:24–41

    Article  CAS  PubMed  Google Scholar 

  • Nickl-Jockschat T, Michel TM (2011) The role of neurotrophic factors in autism. Mol Psychiatry 16:478–490

    Article  CAS  PubMed  Google Scholar 

  • Pavăl DA (2017) Dopamine hypothesis of autism spectrum disorder. Dev Neurosci 39:355–360

    Article  CAS  PubMed  Google Scholar 

  • Ozonoff S, Goodlin-Jones BL, Solomon M (2005) Evidence-based assessment of autism spectrum disorders in children and adolescents. J Clin Child Adolesc Psychol 34:523–540

    Article  PubMed  Google Scholar 

  • Pelleymounter MA, Cullen MJ, Baker MB, Healy D (1999) Glial cell line-derived neurotrophic factor (GDNF) improves spatial learning in aged Fischer 344 rats. Psychobiology 27:397–401

    CAS  Google Scholar 

  • Perry A, Condillac RA, Freeman NL, Dunn-Geier J, Belair J (2005) Multi-site study of the Childhood Autism Rating Scale (CARS) in five clinical groups of young children. J Autism Dev Disord 35:625–634

    Article  PubMed  Google Scholar 

  • Pertusa M, Garcia-Matas S, Mammeri H, Adell A, Rodrigo T, Mallet J et al (2008) Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats. Neurobiol Aging 29:1366–1379

    Article  CAS  PubMed  Google Scholar 

  • Popova NK, Ilchibaeva TV, Naumenko VS (2017) Neurotrophic factors (BDNF and GDNF) and the serotonergic system of the brain. Biochemistry (Mosc) 82:308–317

    Article  CAS  Google Scholar 

  • Rodrigues DH, Rocha NP, Sousa LF, Barbosa IG, Kummer A, Teixeira AL (2014) Circulating levels of neurotrophic factors in autism spectrum disorders. Neuro Endocrinol Lett 35:380–384

    PubMed  Google Scholar 

  • Rojas DC (2014) The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm 121:891–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schopler E, Reichler RJ, Renner BR (1986) The Childhood Autism Rating Scale (CARS) for diagnostic screening and classification in autism. Irvington, New York

    Google Scholar 

  • Shim SH, Hwangbo Y, Yoon HJ, Kwon YJ, Lee HY, Hwang JA, Kim YK (2015) Increased levels of plasma glial-derived neurotrophic factor in children with attention deficit hyperactivity disorder. Nordic J Psychiatry 69:546–551

    Article  Google Scholar 

  • Sinha Y, Silove N, Wheeler D, Williams K (2011) Auditory integration training and other sound therapies for autism spectrum disorders. Cochrane Database Syst Rev (12):CD003681. https://doi.org/10.1002/14651858.CD003681

  • Sinha Y, Silove N, Wheeler D, Williams K (2004) Auditory integration training and other sound therapies for autism spectrum disorders. Cochrane Database Syst Rev (1):CD003681. https://doi.org/10.1002/14651858.CD003681.pub2

  • Sinha Y, Silove N, Wheeler D, Williams K (2006) Auditory integration training and other sound therapies for autism spectrum disorders: a systematic review. Arch Dis Child 91:1018–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skaper SD (2017) Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 151:1–15. https://doi.org/10.1111/imm.12717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokhadze EM, Casanova MF, Tasman A, Brockett S (2016) Electrophysiological and behavioral outcomes of Berard auditory integration training (AIT) in children with autism spectrum disorder. Appl Psychophysiol Biofeedback 41:405–420

    Article  PubMed  Google Scholar 

  • Souza RP, Romano-Silva MA, Lieberman JA, Meltzer HY, MacNeil LT, Culotti JG, Kennedy JL, Wong AH (2010) Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response. J Psychiatr Res 44:700–706

    Article  PubMed  Google Scholar 

  • Tajdaran K, Gordon T, Wood MD, Shoichet MS, Borschel GH (2016) A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts. Acta Biomater 29:62–70

    Article  CAS  PubMed  Google Scholar 

  • Trottier G, Srivastava L, Walker CD (1999) Etiology of infantile autism. A review of recent advances in genetic and neurological research. J Psychiatry Neurosci 24:103–115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsybko AS, Il’chibaeva TV, Kondaurova EM, Bazovkina DV, Naumenko VS (2014) The effect of central administration of the neurotrophic factors BDNF and GDNF on the functional activity and expression of the serotonin 5-HT2A receptors in mice genetically predisposed to depressive-like behavior. Mol Biol 48:983–989

    Article  CAS  Google Scholar 

  • Vlaskamp C, Oranje B, Madsen GF, Møllegaard Jepsen JR, Durston S, Cantio C, Glenthøj B, Bilenberg N (2017) Auditory processing in autism spectrum disorder: mismatch negativity deficits. Autism Res 10:1857–1865

    Article  PubMed  Google Scholar 

  • Voikar V, Rossi J, Rauvala H, Airaksinen MS (2004) Impaired behavioural flexibility and memory in mice lacking GDNF family receptor alpha 2. Eur J Neurosci 20:308–312

    Article  PubMed  Google Scholar 

  • Wang X (2013) Structural studies of GDNF family ligands with their receptors-insights into ligand recognition and activation of receptor tyrosine kinase RET. Biochim Biophys Acta 1834:2205–2212

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Lee LC, Chen YS, Hsu JW (2012) Assessing autistic traits in a Taiwan preschool population: cross-cultural validation of the Social Responsiveness Scale (SRS). J Autism Dev Disord 42:2450–2459

    Article  PubMed  Google Scholar 

  • Ye F, Zhan Q, Xiao W, Sha W, Zhang X (2018) Altered serum levels of glial cell line-derived neurotrophic factor in male chronic schizophrenia patients with tardive dyskinesia. Int J Methods Psychiatr Res 27:e1727. https://doi.org/10.1002/mpr.1727

    Article  PubMed  Google Scholar 

  • Yeh SH, Lin LW, Chuang YK, Liu CL, Tsai LJ, Tsuei FS, Lee MT, Hsiao CY, Yang KD (2015) Effects of music aerobic exercise on depression and brain-derived neurotrophic factor levels in community dwelling women. Biomed Res Int 2015:135893. https://doi.org/10.1155/2015/135893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Tan H, Jiang W, Zuo Z (2014) Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats. Anesthesiology 121:773–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang WR, Hayashi T, Iwai M, Nagano I, Sato K, Manabe Y, Abe K (2001) Time dependent amelioration against ischemic brain damage by glial cell line-derived neurotrophic factor after transient middle cerebral artery occlusion in rat. Brain Res 903:253–256

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Haney MJ, Gupta R, Bohnsack JP, He Z, Kabanov AV, Batrakova EV (2014) GDNF-transfected macrophages produce potent neuroprotective effects in Parkinson’s disease mouse model. PLoS One 9:e106867. https://doi.org/10.1371/journal.pone.0106867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia (award number 08-MED 510 -02).

Author information

Authors and Affiliations

  1. Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Laila Al-Ayadhi

  2. Autism Research and Treatment Center, Riyadh, Saudi Arabia

    Laila Al-Ayadhi

  3. Shaik AL-Amodi Autism Research Chair, King Saud University, Riyadh, Saudi Arabia

    Laila Al-Ayadhi

  4. Central Laboratory, Center for Female Scientific and Medical Colleges, King Saud University, Riyadh, Saudi Arabia

    Afaf El-Ansary

  5. Medicinal Chemistry Department, National Research Centre, Dokki, Cairo, Egypt

    Afaf El-Ansary

  6. CONEM Saudi Autism Research Group, King Saud University, Riyadh, Saudi Arabia

    Afaf El-Ansary

  7. Council for Nutritional and Environmental Medicine (CONEM), Toften 24, 8610, Mo i Rana, Norway

    Geir Bjørklund

  8. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Salvatore Chirumbolo

  9. CONEM Scientific Secretary, Verona, Italy

    Salvatore Chirumbolo

  10. Department of Pediatrics, Faculty of Medicine, Ain Shams University, 17 Asem Abd El-Hamid Street off Makram Ebaid, Nasr City, Cairo, 11511, Egypt

    Gehan Ahmed Mostafa

Authors
  1. Laila Al-Ayadhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Afaf El-Ansary
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geir Bjørklund
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvatore Chirumbolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gehan Ahmed Mostafa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gehan Ahmed Mostafa.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Limitation of the Study

In the present study, the small sample size was a limitation. Therefore, further research, on a large scale, is recommended to study the impact of AIT on plasma levels of GDNF.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Ayadhi, L., El-Ansary, A., Bjørklund, G. et al. Impact of Auditory Integration Therapy (AIT) on the Plasma Levels of Human Glial Cell Line–Derived Neurotrophic Factor (GDNF) in Autism Spectrum Disorder. J Mol Neurosci 68, 688–695 (2019). https://doi.org/10.1007/s12031-019-01332-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-019-01332-w

Keywords

Search

Navigation