Skip to main content
SpringerLink
Log in

Understanding Alterations During Human Brain Development with Molecular Imaging: Role in Determining Serotonin and GABA Mechanisms in Autism

  • Chapter
Book cover The Neurochemical Basis of Autism

  • 1562 Accesses

Abstract

The purpose of this chapter is to present an approach to the understanding of chemical differences in the brains of children with autism and to use to information to design new treatments for autism. The approach is to utilize information about how the processes in the developing brain of an autistic child differs from those in typically developing children discovered through molecular imaging to design new pharmacological treatments to bring brain development in the autistic child back on course.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aman MG (2004) Management of hyperactivity and other acting-out problems in patients with autism spectrum disorder. Semin Pediatr Neurol 11:225–228.

    Article  PubMed  Google Scholar 

  • Bass MP, Menold MM, Wolpert CM, Donelly SL, Ravan SA, Hauser ER, Maddox LO, Vance JM, Abramson RK, Wright HH, Gilbert JR, Cuccaro ML, DeLong GR, Pericak-Vance MA (2000) Genetic studies in autistic disorder and chromosome 15. Neurogenetics 2:219–226.

    Article  CAS  PubMed  Google Scholar 

  • Bennett-Clarke CA, Leslie MJ, Lane RD, Rhoades RW (1994) Effect of serotonin depletion on vibrissae-related patterns in the rat’s somatosensory cortex. J Neurosci 14:7594–7607.

    CAS  PubMed  Google Scholar 

  • Bennett-Clarke CA, Chiaia NL, Rhoades RW (1996) Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites. Brain Res 733:301–306.

    Article  CAS  PubMed  Google Scholar 

  • Blue ME, Erzurumlu RS, Jhaveri S (1991) A comparison of pattern formation by thalamocortical and serotonergic afferents in the rat barrel field cortex. Cereb Cortex 1:380–389.

    Article  CAS  PubMed  Google Scholar 

  • Bostic JQ, King BH (2005) Autism spectrum disorders: emerging pharmacotherapy. Expert Opin Emerg Drugs 10:521–536.

    Article  CAS  PubMed  Google Scholar 

  • Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R (2002) Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7:311–316.

    Article  CAS  PubMed  Google Scholar 

  • Carlson BX, Elster L, Schousboe A (1998) Pharmacological and functional implications of developmentally-regulated changes in GABA(A) receptor subunit expression in the cerebellum. Eur J Pharmacol 352:1–14.

    Article  CAS  PubMed  Google Scholar 

  • Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aguet M, Babinet C, Shih JC, De Maeyer E (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766.

    Article  CAS  PubMed  Google Scholar 

  • Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P (1996) Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16:297–307.

    Article  CAS  PubMed  Google Scholar 

  • Chandana SR, Behen ME, Juhasz C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC (2005) Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci 23:171–182.

    Article  CAS  PubMed  Google Scholar 

  • Chugani HT, Phelps ME, Mazziotta JC (1987) Positron emission tomography study of human brain functional development. Ann Neurol 22:487–497.

    Article  CAS  PubMed  Google Scholar 

  • Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT (1997) Altered serotonin synthesis in the dentato-thalamo-cortical pathway in autistic boys. Ann Neurol 42:666–669.

    Article  CAS  PubMed  Google Scholar 

  • Chugani DC, Muzik O, Behen ME, Rothermel RD, Lee J, Chugani HT (1999) Developmental changes in brain serotonin synthesis capacity in autistic and non-autistic children. Ann Neurol 45:287–295.

    Article  CAS  PubMed  Google Scholar 

  • Chugani DC, Muzik O, Juhasz C, Janisse JJ, Ager J, Chugani HT (2001) Postnatal maturation of human GABAA receptors measured with positron emission tomography. Ann Neurol 49: 618–626.

    Article  CAS  PubMed  Google Scholar 

  • Chugani DC, Pfund Z, Chandana S, Behen ME, Muzik O, Juhasz C, Lee J (2002) GABAA receptors measured with [C-11] flumazenil PET in children with autism, Angelman and Landau-Kleffner syndromes. International Meeting for Autism Research, Orlando, Florida, November 2002.

    Google Scholar 

  • Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 4:928–934.

    Google Scholar 

  • Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E (1998) Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet 62:1077–1083.

    Article  CAS  PubMed  Google Scholar 

  • D‘Amato RJ, Blue ME, Largent BL, Lynch DR, Ledbetter DJ, Molliver ME, Snyder SH (1987) Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas. Proc Natl Acad Sci USA 84:4322–4326.

    Article  PubMed  Google Scholar 

  • DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW (1998) Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 18:8505–8514.

    CAS  PubMed  Google Scholar 

  • DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res 187:207–220.

    Article  CAS  PubMed  Google Scholar 

  • Edagawa Y, Saito H, Abe K (1998a) Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex. Prog Neuropsycholopharmacol Biol Psychiatry 22:983–997.

    Article  CAS  Google Scholar 

  • Edagawa Y, Saito H, Abe K (1998b) 5HT1A receptor-mediated inhibition of long-term potentiation in rat visual cortex. Eur J Pharmacol 349:221–224.

    Article  CAS  PubMed  Google Scholar 

  • Edagawa Y, Saito H, Abe K (1999) Stimulation of the 5HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex. Brain Res 827:225–228.

    Article  CAS  PubMed  Google Scholar 

  • Edagawa Y, Saito H, Abe K (2001) Endogenous serotonin contributes to a developmental decrease in long-term potentiation in the rat visual cortex. J Neurosci 21:1532–1537.

    CAS  PubMed  Google Scholar 

  • Esaki T, Cook M, Shimoji K, Murphy DL, Sokoloff L, Holmes A (2005) Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice. Proc Natl Acad Sci 102:5582–5587.

    Article  CAS  PubMed  Google Scholar 

  • Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810.

    Article  CAS  PubMed  Google Scholar 

  • Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD (2009) GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord 39:223–230. Epub 2008 Sep 23.

    Article  PubMed  Google Scholar 

  • Fitzgerald KK, Sanes DH (1999) Serotonergic modulation of synapses in the developing gerbil lateral superior olive. J Neurophysiol 81:2743–2752.

    CAS  PubMed  Google Scholar 

  • Galter D, Unsiker K (2000) Sequential activation of the 5HT1A serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Mol Cell Neurosci 15:446–455.

    Article  CAS  PubMed  Google Scholar 

  • Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012.

    Article  CAS  PubMed  Google Scholar 

  • Goldman-Rakic, P. S. & Brown, R. M. (1982) Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Dev Brain Res 4:339–349.

    Article  CAS  Google Scholar 

  • Golshani P, Truong H, Jones EG (1997) Developmental expression of GABAA receptor subunit and GAD genes in mouse somatosensory barrel cortex. J Comp Neurol 383:199–219.

    Article  CAS  PubMed  Google Scholar 

  • Goodman C, Shatz C (1993) Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72(Suppl 10), 77–98.

    Article  PubMed  Google Scholar 

  • Guptill JT, Booker AB, Gibbs TT, Kemper TL, Bauman ML, Blatt GJ (2007) [3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study. J Autism Dev Disord 37:911–920.

    Article  PubMed  Google Scholar 

  • Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF (1998) Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282:1504–1508.

    Article  CAS  PubMed  Google Scholar 

  • Holopainen IE, Metsähonkala EL, Kokkonen H, Parkkola RK, Manner TE, Någren K, Korpi ER (2001) Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABAA receptor β3 subunit deletions. Ann Neurol 49:110–113.

    Article  CAS  PubMed  Google Scholar 

  • Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Mäkelä R, Brilliant MH, Hagiwara N, Ferguson C, Snyder K, Olsen RW (1997) Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA 94:4143–4148.

    Article  CAS  PubMed  Google Scholar 

  • Hornung J-P, Fritschy J-M (1996) Developmental profile of GABAA-receptors in the marmoset monkey: Expression of distinct subtypes in pre- and postnatal brain. J Comp Neurol 367:413–430.

    Article  CAS  PubMed  Google Scholar 

  • Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF, Maffei L, Tonegawa S (1999) BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98:739–755.

    Article  CAS  PubMed  Google Scholar 

  • Huntsman MM, Isackson PJ, Jones EG (1994) Lamina-specific expression and activity-dependent regulation of seven GABAA receptor mRNAs in monkey visual cortex. JNeurosci 14:2236–2259.

    CAS  Google Scholar 

  • Huntsman MM, Woods TM, Jones EG (1995) Laminar patterns of expression of GABAA receptor subunit mRNAs in monkey sensory motor cortex. J Comp Neurol 362:565–582.

    Article  CAS  PubMed  Google Scholar 

  • Huntsman MM, Munoz A, Jones EG (1999) Temporal modulation of GABAA receptor subunit gene expression in developing monkey cerebral cortex. Neuroscience 91:1223–1245.

    Article  CAS  PubMed  Google Scholar 

  • Isaac JTR, Crair MC, Nicoll RA, Malenka RC (1997) Silent synapses during development of thalamocortical inputs. Neuron 18:269–280.

    Article  CAS  PubMed  Google Scholar 

  • Kojic L, Dyck R, Gu Q, Douglas RM, Matsubara J, Cynader MS (2000) Columnar distribution of serotonin-dependent plasticity within kitten striate cortex. Proc Natl Acad Sci 97:1841–1844.

    Article  CAS  PubMed  Google Scholar 

  • Kultas-Ilinsky K, Leontiev V, Whiting PJ (1998) Expression of 10 GABAA receptor subunit messenger RNAs in the motor-related thalamic nuclei and basal ganglia of Macaca Mulatta studied with in situ hybridization histochemistry. Neuroscience 85:179–204.

    Article  CAS  PubMed  Google Scholar 

  • Lebrand C, Cases O, Adelbrecht C, Doye A, Alvarez C, Mestikawy SE, Seif I, Gaspar P (1996) Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17:823–835.

    Article  CAS  PubMed  Google Scholar 

  • Li P, Zhou M (1998) Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393:695–698.

    Article  CAS  PubMed  Google Scholar 

  • Lidow MS, Goldman-Rakic PS, Pakic P (1991) Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex. Proc Natl Acad Sci USA 88:10218–10221.

    Article  CAS  PubMed  Google Scholar 

  • Martin ER, Menold MM, Wolpert CM, Bass MP, Donelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA (2000) Analysis of linkage disequilibrium in γ-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 96:43–48.

    Article  PubMed  Google Scholar 

  • Menold MM, Shao Y, Wolpert CM, Donnelly SL, Raiford KL, Martin ER, Ravan SA, Abramson RK, Wright HH, Delong GR, Cuccaro ML, Pericak-Vance MA, Gilbert JR (2001) Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. J Neurogenet 15:245–259.

    Article  CAS  PubMed  Google Scholar 

  • Nishi M, Whitaker-Azmitia PM, Azmitia EC (1996) Enhanced synaptophysin immunoreactivity in rat hippocampal culture by 5-HT 1A agonist, S100b, and corticosteroid receptor agonists. Synapse 23:1–9.

    Article  CAS  PubMed  Google Scholar 

  • Osterheld-Haas MC, Hornung JP (1996) Laminar development of the mouse barrel cortex, effects of neurotoxins against monoamines. Exp Brain Res 110:183–195.

    Article  CAS  PubMed  Google Scholar 

  • Palermo MT, Curatolo P (2004) Pharmacologic treatment of autism. J Child Neurol 19:155–164.

    PubMed  Google Scholar 

  • Posey DJ, McDougle CJ (2001) Pharmacotherapeutic management of autism. Expert Opin Pharmacother 2:587–600.

    Article  CAS  PubMed  Google Scholar 

  • Ramoa AS, Paradiso MA, Freeman RD (1988) Blockade of intracortical inhibition in kitten striate cortex: Effects on receptive field properties and associated loss of ocular dominance plasticity. Exp Brain Res 73:285–298.

    Article  CAS  PubMed  Google Scholar 

  • Reiter HO, Stryker MP (1988) Neural plasticity without postsynaptic action potentials, less active inputs become dominant when kitten visual cortical cells are pharmacologically inhibited. Proc Natl Acad Sci USA 85:3623–3627.

    Article  CAS  PubMed  Google Scholar 

  • Silva AE, Vayego-Lourenco SA, Fett-Conte AC, Goloni-Bertollo EM, Varella-Garcia M (2002) Tetrasomy 15q11–q13 identified by fluorescence in situ hybridization in a patient with autistic disorder. Arq Neuropsiquiatr 60:290–294.

    PubMed  Google Scholar 

  • Sinkkonen ST, Homanics GE, Korpi ER (2003) Mouse models of Angelman syndrome, a neurodevelopmental disorder, display different brain regional GABA(A) receptor alterations. Neurosci Lett 340:205–208.

    Article  CAS  PubMed  Google Scholar 

  • Tecott LH, Logue SF, Wehner JM, Kauer JA (1998) Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice. Proc Natl Acad Sci USA 95:15026–15031.

    Article  CAS  PubMed  Google Scholar 

  • Upton AL, Salichon N, Lebrand C, Ravary A, Blakely R, Seif I, Gaspar P (1999) Excess of serotonin (5-HT) alters the segregation of ipsilateral and contralateral retinal projections in monoamine oxidase A knock-out mice: Possible role of 5-HT uptake in retinal ganglion cells during development. J Neurosci 19:7007–7024.

    CAS  PubMed  Google Scholar 

  • Wolf W, Hicks TP, Albus K (1986) The contribution of GABA-mediated inhibitory mechanisms to visual response properties of neurons in the kitten’s striate cortex. J Neurosci 6:2779–2796.

    CAS  PubMed  Google Scholar 

  • Yan W, Wilson CC, Haring JH (1997) Effects of neonatal serotonin depletion on the development of rat dentate granule cells. Brain Res Dev Brain Res 98:177–184.

    Article  CAS  PubMed  Google Scholar 

  • Yip J, Soghomonian JJ, Blatt GJ (2007) Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol 113:559–568.

    Article  CAS  PubMed  Google Scholar 

  • Yip J, Soghomonian JJ, Blatt GJ (2009) Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res 2:50–59.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Children’s Hospital of Michigan, Detroit, MI, 48201, USA

    Diane C. Chugani

Authors
  1. Diane C. Chugani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diane C. Chugani .

Editor information

Editors and Affiliations

  1. Laboratory for Autism Neuroscience Research, Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118-2526, USA

    Gene J. Blatt

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Chugani, D.C. (2010). Understanding Alterations During Human Brain Development with Molecular Imaging: Role in Determining Serotonin and GABA Mechanisms in Autism. In: Blatt, G.J. (eds) The Neurochemical Basis of Autism. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-1272-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation