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Excitotoxicity in the Pathogenesis of Autism

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Abstract

Autism is a debilitating neurodevelopment disorder characterised by stereotyped interests and behaviours, and abnormalities in verbal and non-verbal communication. It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review.

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References

  • Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R, Martinou JC (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science 277:370–372

    Article  CAS  PubMed  Google Scholar 

  • Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34:325–337

    Article  CAS  PubMed  Google Scholar 

  • Ashcroft FM (2006) From molecule to malady. Nature 440:440–447

    Article  CAS  PubMed  Google Scholar 

  • Babu GN, Bawari M, Ali MM (1994) Lipid peroxidation potential and antioxidant status of circumventricular Organs of rat brain following neonatal monosodium glutamate. Neurotoxicology 15:773–777

    CAS  PubMed  Google Scholar 

  • Baker PF, Naughton MC (1976) Kinetics and energetics of calcium efflux from intact squid giant axons. J Physiol 259:103–144

    CAS  PubMed  Google Scholar 

  • Blaylock RL (2003) The central role of excitotoxicity in autism spectrum disorders. J Am Nutraceut Assoc 6:7–19

    Google Scholar 

  • Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92:7162–7166

    Article  CAS  PubMed  Google Scholar 

  • Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

    Article  CAS  PubMed  Google Scholar 

  • Caldeira MV, Melo CV, Pereira DB, Carvalho RF, Carvalho AL, Duarte CB (2007) BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol Cell Neurosci 35:208–219

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005) International union of pharmacology. XLVIII. Nomenclature and structure–function relationships of voltage-gated calcium channels. Pharmacol Rev 57:411–425

    Article  CAS  PubMed  Google Scholar 

  • Centers for Disease Control and Prevention (2009) Autism information center. http://www.cdc.gov/ncbddd/autism/faq_prevalence.htm. Accessed 27 May 2009

  • Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C (2007) Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol 22(5):574–579

    Article  PubMed  Google Scholar 

  • Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379

    CAS  PubMed  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  CAS  PubMed  Google Scholar 

  • Cohly HH, Panja A (2005) Immunological findings in autism. Int Rev Neurobiol 71:317–341

    Article  CAS  PubMed  Google Scholar 

  • Damme PV, Bogaert E, Dewil M, Hersmus N, Kiraly D, Scheveneels W, Bockx I, Braeken D, Verpoorten N, Verhoeven K, Timmerman V, Herijgers P, Callewaert G, Carmeliet P, Den Bosch LV, Robberecht W (2007) Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci USA 104:14825–14830

    Google Scholar 

  • Deth R et al (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29:190–201

    Article  CAS  PubMed  Google Scholar 

  • Dolmetsch RE, Pajvani U, Fife K, Spotts JM, Greenberg ME (2001) Signaling to the nucleus by an L-type calcium channel calmodulin complex through the MAP kinase pathway. Science 294:333–339

    Article  CAS  PubMed  Google Scholar 

  • Eliasson MJ, Huang Z, Ferrante RJ (1999) Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. J Neurosci 19:59105918

    Google Scholar 

  • Ernfors P, Lee KF, Jaenisch R (1994) Mice lacking brain derived neurotrophic factor develop with sensory deficits. Nature 368:147–150

    Article  CAS  PubMed  Google Scholar 

  • Espey MG, Kustova Y, Sei Y, Basile AS (1998) Extracellular glutamate levels are chronically elevated in the brains of LPBM5-infected mice: a mechanism of retrovirus-induced encephalopathy. J Neurochem 71:2079–2087

    Article  CAS  PubMed  Google Scholar 

  • Farber NB, Newcomer JW, Olney JW (1998) The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer’s disease. Prog Brain Res 116:421–437

    Article  CAS  PubMed  Google Scholar 

  • Farooqui AA, Horrocks LA (1994) Excitotoxicity and neurological disorders: involvement of membrane phospholipids. Int Rev Neurobiol 36:267–323

    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 

  • Fontana A, Constam D, Frei K, Koedel U, Pfister W, Weller M (1996) Cytokines and defense against CNS infection. In: Ransohoff RM, Beneviste EN (eds) Cytokines and the CNS. CRC Press, Boca Raton, pp 187–220

    Google Scholar 

  • Fosslier E (2001) Mitochondrial medicine-molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci 31:25–67

    Google Scholar 

  • Gillberg C, Coleman M (2000) The biology of autistic syndromes, 3rd edn. Mac Keith, London (distributed by Cambridge University Press)

    Google Scholar 

  • Goldberg MP, Choi DW (1993) Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci 13:3510–3524

    CAS  PubMed  Google Scholar 

  • Gottmann K, Mittmann T, Lessmann (2009) BDNF signaling in the formation, maturation and plasticity of glutamatergic and GABAergic synapses. Exp Brain Res 199:203–234

    Article  CAS  PubMed  Google Scholar 

  • Henneberry RC (1989) The role of neuronal energy in neurotoxicity of excitatory amino acids. Neurobiol Aging 10:611613

    Article  Google Scholar 

  • Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC (2000) Cytokine effects on glutamate uptake by human astrocytes. NeuroImmunoModulation 7:153–159

    Article  CAS  PubMed  Google Scholar 

  • Inoue H, Okada Y (2007) Roles of volume-sensitive chloride channel in excitotoxic neuronal injury. J Neurosci 27(6):1445–1455

    Article  CAS  PubMed  Google Scholar 

  • Isackson PJ, Huntsman MM, Murray KD, Gall CM (1991) BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron 6:937–948

    Article  CAS  PubMed  Google Scholar 

  • Jeffs GF, Meloni BP, Bakker AJ, Knuckey NW (2007) The role of the Na(+)/Ca(2+) exchanger (NCX) in neurons following ischemia. J Clin Neurosci 14:507–514

    Article  CAS  PubMed  Google Scholar 

  • Johnston MV (1995) Neurotransmitters and vulnerability of the developing brain. Brain Dev 17:301–306

    Article  CAS  PubMed  Google Scholar 

  • Keller F, Persico AM (2003) The neurobiological context of autism. Mol Neurobiol 28:1–22

    Article  CAS  PubMed  Google Scholar 

  • Kokaia M, Ernfors P, Kokaia Z, Elmer E, Jaenisch R, Lindvall O (1995) Suppressed epileptogenesis in BDNF mutant mice. Exp Neurol 133:215–224

    Article  CAS  PubMed  Google Scholar 

  • Korvatska E, Van de Water J, Anders TF, Gershwin ME (2002) Genetic and immunologic considerations in autism. Neurobiol Dis 9:107–125

    Article  CAS  PubMed  Google Scholar 

  • Koyama R, Yamada MK, Fujisawa S, Katoh-Semba R, Matsuki N, Ikegaya Y (2004) Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus. J Neurosci 24:7215–7224

    Article  CAS  PubMed  Google Scholar 

  • Kramar EA, Chen LY, Lauterborn JC, Simmons DA, Gall CM, Lynch G (2010) BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats. Neurobiol Aging 33(4):708–719

    Article  PubMed  Google Scholar 

  • Lahteinen S, Pitkanen A, Saarelainen T, Nissinen J, Koponen E, Castren E (2002) Decreased BDNF signalling in transgenic mice reduces epileptogenesis. Eur J Neurosci 15:721–734

    Article  PubMed  Google Scholar 

  • Lamb JA, Moore J, Bailey A, Monaco AP (2000) Autism: recent molecular genetic advances. Hum Mol Genet 9:861–868

    Article  CAS  PubMed  Google Scholar 

  • Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, Zheng X, Bennett MV, Zukin RS (2001) Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 4:382–390

    Article  CAS  PubMed  Google Scholar 

  • Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch Eur J Physiol 460:525–542

    Article  CAS  Google Scholar 

  • Laumonnier F, Roger S, Guerin P, Molinari F, M’Rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M et al (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 163:1622–1629

    Article  PubMed  Google Scholar 

  • Lawson K (1996) Potassium channel activation: a potential therapeutic approach? Pharmacol Ther 70:39–63

    Article  CAS  PubMed  Google Scholar 

  • Lawson K (2000) Potassium channel openers as potential therapeutic weapons in ion channel disease. Kidney Int 57:838–845

    Article  CAS  PubMed  Google Scholar 

  • Lees KR (1998) Does neuroprotection improve stroke outcome? Lancet 351:1447–1448

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622

    Article  CAS  PubMed  Google Scholar 

  • Lord C, Cook EH, Leventhal BL, Amaral DG (2000) Autism spectrum disorders. Neuron 28:355–363

    Article  CAS  PubMed  Google Scholar 

  • Madara JC, Levine ES (2008) Presynaptic and postsynaptic NMDA receptors mediate distinct effects of brain-derived neurotrophic factor on synaptic transmission. J Neurophysiol 100(6):3175–3184

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Fu W, Waeg G, Uchida K (1997) 4-hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport 8:2275–2281

    Article  CAS  PubMed  Google Scholar 

  • Mrak RE, Sheng JG, Griffin ST (1995) Glial cytokines in Alzheimer’s disease. Human Pathol 26:816–823

    Article  CAS  Google Scholar 

  • Novelli A, Reilly JA, Lysko PG, Henneberry RC (1988) Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res 451:205–212

    Article  CAS  PubMed  Google Scholar 

  • O’Banion MK (1999) Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. Critical Rev Neurobiol 13:4582

    Google Scholar 

  • Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 165:719721

    Google Scholar 

  • Pencea V, Bingaman VKD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21:6706–6717

    CAS  PubMed  Google Scholar 

  • Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161

    CAS  PubMed  Google Scholar 

  • Portera-Cailliau C, Price DL, Martin LJ (1997) Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum. J Comp Neurol 378:88–104

    Article  CAS  PubMed  Google Scholar 

  • Robbins J (2001) KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther 90:1–19

    Article  CAS  PubMed  Google Scholar 

  • Rogawski MA (1995) Excitatory amino acids and seizures. In: Stone TW (ed) CNS neurotransmitters and neuromodulators: glutamate. CRC Press, Boca Raton, pp 219–237

    Google Scholar 

  • Saito K, Markey SP, Heyes MP (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience 51:25–39

    Article  CAS  PubMed  Google Scholar 

  • Sattler R, Tymianski M (2000) Molecular mechanisms of calcium dependent excitotoxicity (in process citation). J Mol Med 78:3–13

    Article  CAS  PubMed  Google Scholar 

  • Sattler S, Charlton MP, Hafner M, Tymianski M (1998) Distinct influx pathways, not calcium load, determine neuronal vulnerability to calcium neurotoxicity. J Neurochem 71:2349–2364

    Article  CAS  PubMed  Google Scholar 

  • Seal RP, Amara SG (1999) Excitatory amino acid transporters: a family in flux. Ann Rev Pharmacol Toxicol 39:431–456

    Article  CAS  Google Scholar 

  • Scharfman HE (2005) Brain-derived neurotrophic factor and epilepsy—a missing link? Epilepsy Curr 5:83–88

    Article  PubMed  Google Scholar 

  • Shigeri Y, Seal RP, Shimamoto K (2004) Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Rev 45:250–265

    Article  CAS  PubMed  Google Scholar 

  • Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Iyo M, Takei N, Mori N (2006) Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 30(8):1472–1477

    Article  CAS  PubMed  Google Scholar 

  • Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K et al (2004) Ca1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31

    Article  CAS  PubMed  Google Scholar 

  • Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 102:8089–8096

    Article  CAS  PubMed  Google Scholar 

  • Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281:22085–22091

    Article  CAS  PubMed  Google Scholar 

  • Starrett JE, Dworetzky SI, Gribkoff VK (1996) Modulators of large-conductance calcium-activated potassium channels as potential therapeutic targets. Curr Pharm Design 2:413–428

    CAS  Google Scholar 

  • Tuchman R (2003) Autism. Neurol Clin 21(4):915–932

    Article  PubMed  Google Scholar 

  • Tymianski M, Tator CH (1996) Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery 38:1176–1195

    CAS  PubMed  Google Scholar 

  • Tymianski M, Charlton MP, Carlen PL, Tator CH (1993) Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13:2085–2104

    CAS  PubMed  Google Scholar 

  • Vander Jagt DL, Hunsaker LA, Vander Jagt TJ, Gomez MS, Gonzales DM, Deck LM, Royer RE (1997) Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes. Biochem Pharmacol 53:1133–1140

    Article  Google Scholar 

  • Volkmar FR, Pauls D (2003) Autism. Lancet 362(9390):1133–1141

    Article  PubMed  Google Scholar 

  • Walz C, Jüngling K, Lessmann V, Gottmann K (2006) Presynaptic plasticity in an immature neocortical network requires NMDA receptor activation and BDNF release. J Neurophysiol 96:3512–3516

    Article  CAS  PubMed  Google Scholar 

  • Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH (2003) Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry 8:186–194

    Article  CAS  PubMed  Google Scholar 

  • White RJ, Reynolds IJ (1995) Mitochondria and Na/Ca 2+ exchange buffer glutamate induced calcium loads in cultured cortical neurons. J Neurosci 15:1318–1328

    CAS  PubMed  Google Scholar 

  • Xu B, Gottschalk W, Chow A et al (2000) The role of brain derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving trkB. J Neurosci 20:6888–6897

    CAS  PubMed  Google Scholar 

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Acknowledgments

The project was supported by Sultan Qaboos University; Oman in the form of internal grant is gratefully acknowledged (IG/AGR/FOOD/11/02) and also partly supported by the Research Council; Oman (Grant # RC/AGR/FOOD/11/01) as Post-Doctoral fellowship to Dr. Subash S. The scholarship given by Sultan Qaboos University to Vijayan KR is gratefully acknowledged. This work has been also supported by the National Health and Medical Research Council (NHMRC) and by the Rebecca Cooper foundation (Australia). Dr. Nady Braidy is the recipient of an Alzheimer’s Australia Viertel Foundation Postdoctoral Research Fellowship at the University of New South Wales.

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Essa, M.M., Braidy, N., Vijayan, K.R. et al. Excitotoxicity in the Pathogenesis of Autism. Neurotox Res 23, 393–400 (2013). https://doi.org/10.1007/s12640-012-9354-3

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  • DOI: https://doi.org/10.1007/s12640-012-9354-3

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