Skip to main content
    • Aa
    • Aa

Developmental regulation of group I metabotropic glutamate receptors in the premature brain and their protective role in a rodent model of periventricular leukomalacia

  • Lauren L. Jantzie (a1), Delia M. Talos (a1), Debra B. Selip (a1), Li An (a1), Michele C. Jackson (a1), Rebecca D. Folkerth (a2), Wenbin Deng (a3) and Frances E. Jensen (a1)...

Cerebral white matter injury in premature infants, known as periventricular leukomalacia (PVL), is common after hypoxia–ischemia (HI). While ionotropic glutamate receptors (iGluRs) can mediate immature white matter injury, we have previously shown that excitotoxic injury to premyelinating oligodendrocytes (preOLs) in vitro can be attenuated by group I metabotropic glutamate receptor (mGluR) agonists. Thus, we evaluated mGluR expression in developing white matter in rat and human brain, and tested the protective efficacy of a central nervous system (CNS)-penetrating mGluR agonist on injury to developing oligodendrocytes (OLs) in vivo. Group I mGluRs (mGluR1 and mGluR5) were strongly expressed on OLs in neonatal rodent cerebral white matter throughout normal development, with highest expression early in development on preOLs. Specifically at P6, mGluR1 and mGLuR5 were most highly expressed on GalC-positive OLs compared to neurons, axons, astrocytes and microglia. Systemic administration of (1S,3R) 1-aminocyclopentane-trans-1,3,-dicarboxylic acid (ACPD) significantly attenuated the loss of myelin basic protein in the white matter following HI in P6 rats. Assessment of postmortem human tissue showed both mGluR1 and mGluR5 localized on immature OLs in white matter throughout development, with mGluR5 highest in the preterm period. These data indicate group I mGluRs are highly expressed on OLs during the peak period of vulnerability to HI and modulation of mGluRs is protective in a rodent model of PVL. Group I mGluRs may represent important therapeutic targets for protection from HI-mediated white matter injury.

Corresponding author
Correspondence should be addressed to: Frances E. Jensen, Department of Neurology, Children's Hospital Boston, CLS 14073, 300 Longwood Avenue, Boston, MA 02115, USA phone: 617-919-2445 fax: 617-919-2769 email:
Hide All
S.A. Back , A. Riddle and M.M. McClure (2007) Maturation-dependent vulnerability of perinatal white matter in premature birth. Stroke 38, 724730.

M.F. Bear (2005) Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes, Brain and Behaviour 4, 393398.

K. Biber , D.J. Laurie , A. Berthele , B. Sommer , T.R. Tolle , P.J. Gebicke-Harter (1999) Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia. Journal of Neurochemistry 72, 16711680.

K. Boer , F. Encha-Razavi , M. Sinico and E. Aronica (2010) Differential distribution of group I metabotropic glutamate receptors in developing human cortex. Brain Research 1324, 2433.

A.M. Butt (2006) Neurotransmitter-mediated calcium signaling in oligodendrocyte physiology and pathology. Glia 54, 666675.

K.R. Byrnes , D.J. Loane and A.I. Faden (2009a) Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders. Neurotherapeutics 6, 94107.

J.M. Dean , M.D. Moravec , M. Grafe , N. Abend , J. Ren , X. Gong (2011) Strain-specific differences in perinatal rodent oligodendrocytes lineage progression and its correlation with human. Developmental Neuroscience, doi: 10.1159/000327242. Epub ahead of Print, August 24, 2011.

J. Drouin-Ouellet , A.-L. Bownell , M. Saint-Pierre , C. Fasano , V. Emond , L.-E. Trudeau (2011) Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions. Glia 59, 188199.

F. Ferraguti and R. Shigemoto (2006) Metabotropic glutamate receptors. Cell and Tissue Research 326, 483504.

D. Ferriero (2004) Neonatal brain injury. New England Journal of Medicine 351, 19851995.

R.D. Folkerth , R.L. Haynes , N.S. Borenstein , R.A. Belliveau , F. Trachtenberg , P.A. Rosenberg (2004) Developmental lag in superoxide dismutases relative to other anti-oxidant enzymes in premyelinated human telencephalic white matter. Journal of Neuropathology and Experimental Neurology 63, 990999.

P.L. Follett , W. Deng , W. Dai , D.M. Talos , L.J. Massillon , P.A. Rosenberg (2004) Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. Journal of Neuroscience 24, 44124420.

R.L. Haynes , R.D. Folkerth , R.J. Keefe , I. Sung , L.I. Swzeda , P.A. Rosenberg (2003) Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. Journal of Neuropathology and Experimental Neurology 62, 441450.

C.W. Hodge , M.F. Miles , A.C. Sharko , R.A. Stevenson , J.R. Hillmann , V. Lepoutre (2006) The mGluR antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-admnistration in C57BL/6J mice. Psychopharmacology 183, 429438.

L.L. Jantzie and K.G. Todd (2010) Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia–ischemia in neonatal rats. Journal of Psychiatry and Neuroscience 35, 2032.

F. Jensen (2006) Developmental factors regulating susceptibility to perinatal brain injury and seizures. Current Opinion in Pediatrics 18, 628633.

E.E. Kelland and N.J. Toms (2001) Group I metabotropic glutamate receptors limit AMPA receptor-mediated oligodendrocyte progenitor cell death. European Journal of Pharmacology 424, R3R4.

H.C. Kinney and S.A. Back (1998) Human oligodendroglial development: relationship to periventricular leukomalacia. Seminars in Pediatric Neurology 5, 180189.

K. Kobaly , M. Schluchter , N. Minich , H. Friedman , H.G. Taylor , D. Wilson-Costello (2008) Outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia: effects of practice changes in 2000 to 2003. Pediatrics 121, 7381.

B. Larroque , P.Y. Ancel , S. Marret , L. Marchand , M. Andre , C. Arnaud (2008) Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 371, 813820.

M. Lechpammer , S.M. Manning , F. Samonte , J. Nelligan , E. Sabo , D.M. Talos (2008) Minocycline treatment following hypoxic/ischaemic injury attenuates white matter injury in a rodent model of periventricular leukcomalacia. Neuropathology and Applied Neurobiology 34, 379393.

D. Lojkova and P. Mares (2005) Anticonvulsant action of an antagonist of metabotropic glutamate receptor mGluR5 MPEP in immature rats. Neuropharmacology 49, 219229.

C. Luscher and K.M. Huber (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445459.

K. Luyt , A. Varadi , C.F. Durant and E. Molnar (2006) Oligodendroglial metabotropic glutamate receptors are developmentally regulated and involved in the prevention of apoptosis. Journal of Neurochemistry 99, 641656.

S.M. Manning , D.M. Talos , C. Zhou , D.B. Selip , H.K. Park , C.J. Park (2008) NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia. Journal of Neuroscience 28, 66706678.

J.A. Martin , H.C. Kung , T.J. Mathews , D.L. Hoyert , D.M. Strobino , B. Guyer (2008) Annual summary of vital statistics: 2006. Pediatrics 121, 788801.

J.W. McDonald and M.V. Johnston (1990) Physiological and pathological roles of excitatory amino acids during central nervous system development. Brain Research. Brain Research Reviews 15, 4170.

M.F. Olive (2009) Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Current Drug Abuse Reviews 2, 8398.

E.M. Snyder , B.D. Philpot , K.M. Huber , X. Dong , J.R. Fallon and M.F. Bear (2001) Internalization of ionotropic glutamate receptors in response to mGluR activation. Nature Neuroscience 4, 10791085.

J. Ure , M. Baudry and M. Perassolo (2006) Metabotropic glutamate receptors and epilepsy. Journal of the Neurological Sciences 247, 19.

R.C. Vannucci (2000) Hypoxic-ischemic encephalopathy. American Journal of Perinatology 17, 113119.

J.J. Volpe (2009) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurology 8, 110124.

H. Wake , P.R. Lee and R.D. Fields (2011) Control of local protein synthesis and initial events in myelination by action potentials. Science 333, 16471651.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Neuron Glia Biology
  • ISSN: 1740-925X
  • EISSN: 1741-0533
  • URL: /core/journals/neuron-glia-biology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Jensen Supplementary Figures
Jensen Supplementary Figures

 PDF (212 KB)
212 KB
Supplementary Materials

Jensen Supplementary Figure Legends
Jensen Supplementary Figure Legends

 Word (20 KB)
20 KB


Full text views

Total number of HTML views: 2
Total number of PDF views: 9 *
Loading metrics...

Abstract views

Total abstract views: 169 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 18th October 2017. This data will be updated every 24 hours.