Top

Published in:

01-05-2013 | Review Article

Excitotoxicity in the Pathogenesis of Autism

Authors: M. M. Essa, N. Braidy, K. R. Vijayan, S. Subash, G. J. Guillemin

Published in: Neurotoxicity Research | Issue 4/2013

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.

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 277:370–372CrossRefPubMed

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

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

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

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

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

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 92:7162–7166CrossRefPubMed

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

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 35:208–219CrossRefPubMed

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 57:411–425CrossRefPubMed

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):574–579CrossRefPubMed

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

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

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

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

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

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 294:333–339CrossRefPubMed

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

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

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 71:2079–2087CrossRefPubMed

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

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

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 52:805–810CrossRefPubMed

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

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

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

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 13:3510–3524PubMed

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

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

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

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

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 6:937–948CrossRefPubMed

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 14:507–514CrossRefPubMed

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

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

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

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

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 24:7215–7224CrossRefPubMed

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):708–719CrossRefPubMed

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

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

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 4:382–390CrossRefPubMed

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

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 163:1622–1629CrossRefPubMed

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

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

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

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

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

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):3175–3184CrossRefPubMed

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 8:2275–2281CrossRefPubMed

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

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 451:205–212CrossRefPubMed

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

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

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 21:6706–6717PubMed

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

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 378:88–104CrossRefPubMed

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

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

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

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

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

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

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

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

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):1472–1477CrossRefPubMed

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 119:19–31CrossRefPubMed

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 102:8089–8096CrossRefPubMed

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

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

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

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 38:1176–1195PubMed

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

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 53:1133–1140CrossRef

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

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 96:3512–3516CrossRefPubMed

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 8:186–194CrossRefPubMed

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

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 20:6888–6897PubMed

Title: Excitotoxicity in the Pathogenesis of Autism
Authors: M. M. Essa
N. Braidy
K. R. Vijayan
S. Subash
G. J. Guillemin
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Neurotoxicity Research / Issue 4/2013
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-012-9354-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Excitotoxicity in the Pathogenesis of Autism

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2013

Excitotoxicity Through NMDA Receptors Mediates Cerebellar Granule Neuron Apoptosis Induced by Prion Protein 90-231 Fragment

Regulation of FMO and PON Detoxication Systems in ALS Human Tissues

α-Synuclein Protects Neurons from Apoptosis Downstream of Free-Radical Production Through Modulation of the MAPK Signalling Pathway

Pressor Response to Oral Tyramine and Monoamine Oxidase Inhibition During Treatment with Ralfinamide (NW-1029)

Effect of l-Tyrosine In Vitro and In Vivo on Energy Metabolism Parameters in Brain and Liver of Young Rats

Quercetin Protects Against Chronic Aluminum-Induced Oxidative Stress and Ensuing Biochemical, Cholinergic, and Neurobehavioral Impairments in Rats