title: The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia.
abstract: BACKGROUND
  Periventricular leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL.
  
  
  RESULTS
  In this study, using a mouse model of PVL, we sought to test the hypothesis that PVL-like injury affects the different components of the thalamocortical circuitry that can be defined by vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2), both of which are required for glutamatergic synaptic transmission in the central nervous system. We combined immunocytochemistry and immuno-electron microscopy to investigate changes in cortico-thalamic synapses which were specifically identified by vGluT1 immunolabeling. We found that a drastic reduction in the density of vGluT1 labeled profiles in the somatosensory thalamus, with a reduction of 72-74 % in ventroposterior (VP) nucleus and a reduction of 42-82 % in thalamic reticular nucleus (RTN) in the ipsilateral side of PVL mice. We further examined these terminals at the electron microscopic level and revealed onefold-twofold decrease in the sizes of vGluT1 labeled corticothalamic terminals in VP and RTN. The present study provides anatomical and ultrastructural evidence to elucidate the cellular mechanisms underlying alteration of thalamic circuitry in a mouse model of PVL, and reveals that PVL-like injury has a direct impact on the corticothalamic projection system.
  
  
  CONCLUSIONS
  Our findings provide the first set of evidence showing that the thalamocortical circuitry is affected and vulnerable in PVL mice, supporting a working model in which vGluT1 defined corticothalamic synapses are altered in PVL mice, and vGluT2 defined thalamocortical synapses are associated with such changes, leading to the compromised thalamocortical circuitry in the PVL mice. Our study demonstrates that the thalamocortical circuitry is highly vulnerable to hypoxia-ischemia in the PVL model, thus identifying a novel target site in PVL pathology.
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. xliu@ucdavis.edu.|Center for Neuroscience, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. xliu@ucdavis.edu.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. yshen@ucdavis.edu.|Institute for Pediatric Regenerative Medicine, School of Medicine, University of California, Davis, CA, 95817, USA. yshen@ucdavis.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Center for Neuroscience, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. depleasure@ucdavis.edu.|Institute for Pediatric Regenerative Medicine, School of Medicine, University of California, Davis, CA, 95817, USA. depleasure@ucdavis.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. wbdeng@ucdavis.edu.|Center for Neuroscience, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. wbdeng@ucdavis.edu.|Institute for Pediatric Regenerative Medicine, School of Medicine, University of California, Davis, CA, 95817, USA. wbdeng@ucdavis.edu.|Medical College, Hubei University of Arts and Science, Xiangyang, Hubei, China. wbdeng@ucdavis.edu.|Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, 2425 Stockton Blvd., Room 653, Sacramento, CA, 95817, USA. wbdeng@ucdavis.edu.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure*; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D007969:Leukomalacia, Periventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure*; D013788:Thalamus / Q000378:metabolism / Q000648:ultrastructure*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2