Neurotransmitters and vulnerability of the developing brain

  • Michael V. Johnston
    Corresponding author. Fax: (1) (410) 550-9524.
    Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, and the Kennedy Krieger Institute, 707 N. Broadway Room 506, Baltimore, MD 21205,USA
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      The immature human brain undergoes remarkable organizational changes during intrauterine and postnatal life. These changes create potential temporal ‘windows’ of selective vulnerability to damage. For example, the temporary germinal matrix is vulnerable to hemorrhage in the third trimester fetus and premature infant. The immature oligodendroglia present in developing white matter of the fetus are also vulnerable to injury producing periventricular leukomalacia. Similar changes take place in the synapses that make up the infant's neuronal circuitry. In human cerebral cortex, synapses are produced in greater than adult numbers by postnatal age 2 years and then reduced over the next decade. Over the same period receptors for glutamate, the most important excitatory neurotransmitter, change their characteristics to allow them to participate in activity dependent synaptic plasticity. For example, the immatureN-methyl-d-aspartate (NMDA) type glutamate receptor/channel complex, which plays important roles in long term potentiation (LTP), neuronal migration and synaptic pruning, contains subunits that allow the channel to be opened more easily for a longer period than adult channels. These developmental changes make the immature brain selectively vulnerable to NMDA receptor overstimulation that can occur during hypoxia-ischemia and other insults. Several types of neuropathology in the developing brain can be understood on the basis of these organizational principles.



        • Gilles F.H.
        • Leviton A.
        • Dooling E.C.
        The developing human brain.
        in: John Wright, Boston1983: 349
        • Volpe J.J.
        Intraventricular hemorrhage in the premature infant. Current concepts, part II.
        Ann Neurol. 1989; 25: 109-116
        • Thompson C.B.
        Apoptosis in the pathogenesis and treatment of disease.
        Science. 1995; 267: 1456-1462
        • Huttenlocher P.R.
        • Courten C.
        The development of synapses in striate cortex of man.
        Hum Neurobiol. 1987; 6: 1-9
        • Kostovic I.
        • Lukinovic N.
        • Judas M.
        Structural basis of the developmental plasticity in the human cerebral cortex: the role of the transient subplate zone.
        Metab Brain Dis. 1989; 4: 17-23
        • Thomas L.
        The fragile species.
        Charles Scribner, New York1992
        • Oka A.
        • Belliveau M.J.
        • Rosenberg P.A.
        • Volpe J.J.
        Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms and prevention.
        J Neurosci. 1993; 13: 1441-1453
        • Johnston M.V.
        • Trescher W.H.
        • Taylor G.A.
        Hypoxic and ischemic CNS disorders in infants and children.
        Adv Pediat. 1995; 42: 1-45
        • Banker B.Q.
        • Larroche J.L.
        PVL of infancy: a form of neonatal anoxic encephalopathy.
        Arch Neurol. 1962; 7: 386-410
        • Kuban K.C.K.
        • Leviton A.
        Cerebral palsy.
        New Engl J Med. 1994; 330: 188-194
        • Barkovich A.J.
        MR and CT evaluation of profound neonatal and infantile asphyxia.
        AJNR. 1992; 13: 959-972
        • Chugani H.T.
        • Phelps M.E.
        • Mazziotta J.C.
        Positron emission tomography study of human brain functional development.
        Ann Neurol. 1987; 22: 487-497
        • McDonald J.W.
        • Johnston M.V.
        Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.
        Brain Res Rev. 1990; 15: 41-70
        • Choi D.W.
        • Rothman S.W.
        The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death.
        Annu Rev Neurosci. 1990; 13: 171-182
        • Olney J.W.
        Neurotoxicity of excitatoty amino acids.
        in: McGeer E.G. Olney J.W. McGeer P.L. Kainic acid as a tool in neurobiology. Raven Press, New York1978: 95-121
        • Fonnum F.
        Glutamate: a neurotransmitter in mammalian brain.
        J Neurochem. 1984; 42: 1-11
        • Monaghan D.T.
        • Bridges R.J.
        • Cotman C.W.
        The excitatory amino acid receptors: their classes, pharmacology and distinct properties in the function of the central nervous system.
        Annu Rev Pharmacol Toxicol. 1989; 29: 365-402
        • Berridge M.J.
        Inositol triphosphate and calcium signaling.
        Nature. 1993; 361: 347-350
        • Nakanishi W.
        Molecular diversity of glutamate receptors and implication for brain function.
        Science. 1992; 258: 597-603
        • DeLorey T.M.
        • Olsen R.W.
        GABA and glycine.
        in: Siegel G.J. Agranoff B.W. Albers R.W. Molinoff P.B. Basic neurochemistry. Raven Press, New York1994: 389-399
        • Baumeister F.A.M.
        • Gsell W.
        • Shin Y.S.
        • Egger J.
        Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine.
        Pediatrics. 1994; 94: 318-321
        • White R.J.
        • Reynolds I.J.
        Mitochondria and Na+/CA2+ exchange buffer glutamate induced calcium loads in cultured cortical neurons.
        J Neurosci. 1995; 15: 1318-1328
        • Benveniste H.
        • Drejer J.
        • Schousboe A.
        • Diemer N.H.
        Elevation of the extracellular concentration of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.
        J Neurochem. 1984; 43: 1369-1374
        • Hagberg H.
        • Anderson D.
        • Kjellman I.
        • Thiringer K.
        • Thordstein M.
        Extracellular overflow of glutamate, aspartate, GABA, taurine, in the cortex and basal ganglia of fetal hypoxia during hypoxia-ischemia.
        Neurosci Lett. 1987; 78: 311-317
        • Silverstein F.S.
        • Buchanan K.
        • Johnston M.V.
        Perinatal hypoxia-ischemia disrupts high affinity 3H-glutamate uptake into synaptosomes.
        J Neurochem. 1986; 47: 1614-1619
        • Novelli A.
        • Reilly J.A.
        • Lysko P.G.
        • Henneberry R.C.
        Glutamate becomes neurotoxic via the NMDA receptor when intracellular energy levels are reduced.
        Brain Res. 1988; 451: 205-212
        • Riepe M.W.
        • Hori N.
        • Rudolph A.C.
        • Carpenter D.O.
        Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation.
        Neuroscience. 1995; 64: 91-97
        • Lipton S.A.
        • Rosenberg P.A.
        Excitatory amino acids as a final common pathway for neurologic disorders.
        New Engl J Med. 1994; 330: 613-622
        • Rosenbaum D.M.
        • Michaelson M.
        • Batter D.K.
        • Doshi P.
        • Kessler J.A.
        Evidence for hypoxia-induced, programmed cell death of cultured neurons.
        Ann Neurol. 1994; 36: 864-870
        • Coyle J.T.
        • Puttfarcken P.
        Oxidative stress, glutamate and neurodegenerative disorders.
        Science. 1993; 262: 689-695
        • Greenlund L.J.S.
        • Deckwerth T.L.
        • Johnson E.M.
        Superoxide dismutase delays neuronal apoptosis: a role or reactive oxygen species in programmed neuronal death.
        Neuron. 1995; 14: 303-315
        • Tsumoto T.
        • Hagihara K.
        • Soto H.
        • Hata Y.
        NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats.
        Nature. 1987; 327: 513-514
        • Tremblay E.
        • Roisin M.P.
        • Represa A.
        • Charriaut-Marlangue G.
        • Ben-A.ri Y.
        Transient increased density of NMDA binding sites in the developing rat hippocampus.
        Brain Res. 1988; 461: 393-396
        • McDonald J.W.
        • Johnston M.V.
        • Young A.B.
        Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus.
        Exp Neurol. 1990; 110: 237-247
        • Chen C.-K.
        • Silverstein F.S.
        • Fisher S.K.
        • Statman D.
        • Johnston M.V.
        Perinatal hypoxic-ischemic brain injury enhances quisqualic acid-stimulated phosphoinositide turnover.
        J Neurochem. 1988; 51: 353-359
        • Blue M.E.
        • Johnston M.V.
        The ontogeny of glutamate receptors in rat barrel field cortex.
        Dev Brain Res. 1995; 84: 11-25
        • Pellegrini G.D.
        • Bennett M.
        • Zukin R.S.
        Differential expression of three glutamate receptor genes in the developing rat brain: an in situ hybridization study.
        in: 2nd edn. Proc Natl Acad Sci USA. 88. 1991: 4157-4161
        • Barnashev N.
        • Schoepfer R.
        • Monyer H.
        Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor.
        Science. 1992; 257: 1415-1419
        • Cha J.-H.J.
        • Kinsman S.L.
        • Johnston M.V.
        RNA editing of a human glutamate receptor subunit.
        Mol Brain Res. 1994; 22: 323-328
        • Burgard E.C.
        • Habitz J.J.
        Developmental changes in NMDA and non-NMDA receptor-mediated synaptic potentials in rat neocortex.
        J Neurophysiol. 1993; 69: 230-240
        • Morrisett R.A.
        • Mott D.D.
        • Lewis D.V.
        • Wilson W.A.
        • Swartzwelder H.S.
        Reduced sensitivity of the NMDA component of synaptic transmission to magnesium in hippocampal slices from immature rats.
        Dev Brain Res. 1990; 56: 257-262
        • Kato N.
        • Yoshimura H.
        Reduced Mg2+ block of NMDA receptor-mediated synaptic potentials in developing visual cortex.
        in: 2nd edn. Proc Natl Acad Sci USA. 90. 1993: 7114-7118
        • Williams K.
        • Romano C.
        • Dichter M.A.
        • Molinoff P.B.
        Modulation of the NMDA receptor by polyamines.
        Life Sci. 1991; 48: 469-498
        • Sheng M.
        • Cummings J.
        • Rolau L.A.
        • Jan Y.N.
        • Jan L.Y.
        Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.
        Nature. 1994; 368: 144-147
        • Monyer H.
        • Burnashev N.
        • Laurie D.J.
        • Sakmann B.
        • Seeburg P.H.
        Development and regional expression in the rat brain and functional properties of four NMDA receptors.
        Neuron. 1993; 12: 529-540
        • Rabacchi S.
        • Bailly Y.
        • Delhaye-Bouchard N.
        • Mariani J.
        Involvement of NMDA receptors in synapse elimination during cerebellar development.
        Science. 1992; 256: 1823-1825
        • Ikonomidou C.
        • Mosinger J.L.
        • Shahid Salles K.
        Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to NMDA neurotoxicity.
        J Neurosci. 1989; 9: 2809-2818
        • Trescher W.H.
        • McDonald J.W.
        • Johnston M.V.
        Quinolinate-induced injury is enhanced in developing rat brain.
        Dev Brain Res. 1994; 83: 224-232
        • McDonald J.W.
        • Silverstein F.S.
        • Cardona D.
        • Hudson C.
        • Chen R.
        • Johnston M.V.
        Systemic administration of MK-801 protects against NMDA and quisqualate-mediated neurotoxicity in perinatal rats.
        Neuroscience. 1990; 36: 589-599
        • McDonald J.W.
        • Trescher W.H.
        • Johnston M.V.
        Susceptibility of brain to AMPA induced neurotoxicity transiently peaks during early postnatal development.
        Brain Res. 1992; 583: 54-70
        • Campochiaro P.
        • Coyle J.T.
        Ontogenic development of kainate neurotoxicity: correlates with glutamatergic innervation.
        in: 2nd edn. Proc Natl Acad Sci USA. 75. 1978: 2025-2029
        • McDonald J.W.
        • Fix A.S.
        • Tizzano J.P.
        • Schoepp D.D.
        Seizures and brain injury in neonatal rats induced by 1S,3R-ACPD, a metabotropic glutamate receptor agonist.
        J Neurosci. 1993; 13: 4445-4455