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Glutamate receptors: the cause or cure in perinatal white matter injury?

Published online by Cambridge University Press:  05 January 2012

R. Douglas Fields
R. Douglas Fields*
Affiliation:
Nervous System Development and Plasticity Section, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
*
Correspondence should be addressed to: R. Douglas Fields, Nervous Systems Development & Plasticity Section, National Institutes of Health, NICHD, Building 35, Room 2A211, MSC 3713, 35 Lincoln Drive, Bethesda, MD 20892, USA phone: +1 301 480 3209 email: fieldsd@mail.nih.gov
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Abstract

Glutamate toxicity from hypoxia-ischaemia during the perinatal period causes white matter injury that can result in long-term motor and intellectual disability. Blocking ionotropic glutamate receptors (GluRs) has been shown to inhibit oligodendrocyte injury in vitro, but GluR antagonists have not yet proven helpful in clinical studies. The opposite approach of activating GluRs on developing oligodendrocytes shows promise in experimental studies on rodents as reported by Jartzie et al., in this issue. Group I metabotropic glutamate receptors (mGluRs) are expressed transiently on developing oligodendrocytes in humans during the perinatal period, and the blood–brain-barrier permeable agonist of group I mGluRs, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), reduces white matter damage significantly in a rat model of perinatal hypoxia-ischaemia. The results suggest drugs activating this class of GluRs could provide a new therapeutic approach for preventing cerebral palsy and other neurological consequences of diffuse white matter injury in premature infants.

Keywords

Paraventricular leuckomalaciacerebral palsyhypoxiapremature infantsglutamate toxicityaxon-oligodendrocyte signallingmyelination

Information

Type
Research Article
Information
Neuron Glia Biology , Volume 6 , Issue 4 , November 2010 , pp. 209 - 211
Copyright
Copyright © Cambridge University Press 2011

INTRODUCTION

Hypoxia-ischaemia (HI) is a common cause of brain damage in premature and term infants. Cerebral palsy, epilepsy, learning disorders, intellectual disability and other neurological difficulties are the life-long consequences for many of the 63,000 infants born annually with very low birth weight as a consequence of underdeveloped pulmonary function in preterm infants (Kobaly et al., Reference Kobaly, Schluchter, Minich, Friedman, Taylor and Wilson-Costello2008; Martin et al., Reference Martin, Kung, Mathews, Hoyert, Strobino and Guyer2008; Volpe, Reference Volpe2009) in addition to infants suffering asphyxia at birth (Holopainen and Lauren, Reference Holopainen and Lauren2011). Major motor deficits including cerebral palsy are present in 5–10% of very low birth weight babies (Allin et al., Reference Allin, Walshe, Fern, Nosarti, Cuddy and Rifkin2008; Volpe, Reference Volpe2009). Many biological processes are susceptible to hypoxic injury during this developmental period, but injury to white matter, termed periventricular leukomalacia (PVL) or diffuse white matter injury, is the most prevalent effect. Death of oligodendrocytes and impairment of myelination are a primary pathophysiological basis for perinatal brain injuries because this developmental period coincides with a vulnerable time when oligodendrocyte precursors are proliferating and immature oligodendrocytes are differentiation and beginning to myelinate axons (Back et al., Reference Back, Luo, Borenstein, Levine, Volpe and Kinney2001).

It is well established that the increase in extracellular glutamate during HI initiates excitotoxic injury and cell death (reviewed see Bakiri et al., Reference Bakiri, Burzomato, Frugier, Hamilton, Karadottir and Attwell2009; Holopainen and Lauren, Reference Holopainen and Lauren2011; Matute, Reference Matute2011), which is why the study by Jantzie et al. (in this issue of Neuron Glia Biology), is noteworthy. It shows that activating a specific type of glutamate receptor (GluR) on developing oligodendrocytes cuts white matter injury in half in a rat model of PVL. High concentrations of agonists for 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors are toxic to oligodendrocytes in culture (Yoshioka et al., Reference Yoshioka, Hardy, Younkin, Grinspan, Stern and Pleasure1995) and in optic nerve (Matute et al., Reference Matute, Sanchez-Gomez, Martinez-Millan and Miledi1997) and other white matter tracts in vivo (McDonald et al., Reference McDonald, Althomsons, Hyrc, Choi and Goldberg1998; Follett et al., Reference Follett, Rosenberg, Volpe and Jensen2000). N-Methyl-D-aspartate (NMDA) receptor activation also damages oligodendrocytes (Karadottir et al., Reference Karadottir, Cavelier, Bergersen and Attwell2005; Salter and Fern, Reference Salter and Fern2005; Micu et al., Reference Micu, Jiang, Coderre, Ridsdale, Zhang and Woulfe2006; Bakiri et al., Reference Bakiri, Hamilton, Karadottir and Attwell2008; Manning et al., Reference Manning, Talos, Zhou, Selip, Park and Park2008). Calcium influx through the NMDA receptor and through AMPA receptors lacking the GluR2 subunit (Li and Stys, Reference Li and Stys2000) is thought to initiate the deleterious effects of high levels of extracellular glutamate. Removal of extracellular calcium or application of AMPA receptor antagonists protects oligodendrocytes from HI injury (Yoshioka et al., Reference Yoshioka, Hardy, Younkin, Grinspan, Stern and Pleasure1995; Fern and Moller, Reference Fern and Moller2000; Tekkok and Goldberg, Reference Tekkok and Goldberg2001), but the consequences of activating metabotropic glutamate receptors (mGluRs) in oligodendrocytes is not well understood. In a brief report in 2001, Kelland and Toms (Reference Kelland and Toms2001) showed that mGluR agonists limited kainate-induced oligodendrocyte death, and in 2006 Luyt et al. (Reference Luyt, Váradi, Durant and Molnár2006) showed that activation of mGluR5 protects oligodendrocyte progenitor cells (OPCs) and oligodendrocytes from staurosporine-induced apoptosis.

In their studies, Jantzie et al. (p. xx of this issue) show that mGluR1 and mGluR5 are present in human and rodent white matter during this critical perinatal period for white matter development, and that expression of these receptors is regulated developmentally. In white matter, mGluR1 and mGluR5 are prominently localized on cell bodies of galactosylceramidase (GalC)-positive oligodendrocytes at early ages, but at later ages the receptors become expressed almost exclusively on oligodendrocyte cell processes. At the perinatal period when expression of mGluR1 and mGluR5 peaks in white matter, these receptors are minimally present on microglia and astrocytes, but at later ages (second postnatal week) expression increases on these non-myelinating glia as expression diminishes on GalC-positive oligodenrocytes. Neuronal expression of mGluRs is also lower during the period of peak mGluR expression in oligodendrocytes. These cellular differences in mGluR expression provide the opportunity for preferentially targeting oligodendrocytes during the perinatal period with drugs acting on these receptors.

Previous in vitro studies by these investigators had shown that activating group I mGluRs with ACPD (1-aminocyclopentane-trans-1,3,-dicarboxylic acid) or DHPG (3,5-dihydroxyphenylglycine) protected oligodendrocytes from oxygen and glucose deprivation through intracellular signalling pathways that maintain glutathione (an antioxidant), decreasing production of damaging reactive oxygen species (Deng et al., Reference Deng, Wang, Rosenberg, Volpe and Jensen2004). Here the authors report that systemically administering ACPD, a brain-permeable compound, significantly attenuated white matter injury in a rat model of PVL. The treatment caused no significant increase in seizures, presumably because of the low expression of mGluRs on neurons at this age. Thus, group I mGluRs may represent a therapeutic target for protection from HI-mediated white matter injury during the perinatal period.

Further research will be necessary to determine the detailed mechanisms by which mGluR activation protects against hypoxia-induced white matter injury, because HI injury in the perinatal period is a complex multifactorial pathology, and mGluR receptors are expressed on other cells. One intriguing possibility is that in addition to promoting survival of oligodendrocytes, mGluR activation might stimulate the formation of myelin. This possibility is suggested by new studies showing that the initial events in myelination, including formation of oligodendrocyte-axon signalling domains and local translation of myelin basic protein, are stimulated by vesicular release of glutamate from axons firing action potentials (Wake et al., Reference Wake, Lee and Fields2011). Pharmacological studies implicate both NMDA and mGluR receptors in this activity-dependent mechanism, but inhibiting mGluR receptors independently of NMDA receptors reduced local translation of MBP by 50% (Wake et al., Reference Wake, Lee and Fields2011), indicating a significant involvement of mGluRs on oligodendrocyte cell processes in cell–cell signalling initiating myelination of specific axons.

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