X hits on this document





8 / 9

differentiation, and maintenance of function in differ- ent neuronal populations (44, 47). BDNF is a critical regulator of transcription-dependent adaptive neuro- nal responses, such as LTP (48, 49). Earlier studies have shown that activation of NMDARs lead to increased expression of BDNF (50, 51). This effect appears to involve neuronal rather than astrocytic release of BDNF (52, 53). Therefore, the results of the present study raise the following hypothesis as for the consequences of DCS injection; first, DCS activates NMDARs and as a result improves channel function, either by increasing the number of channels on the membrane or increas- ing the activity of existing channels, or both. Second, increased NMDARs channel activity leads to an increase in BDNF levels, which initiates a positive feedback loop to further enhance the function of hippocampal NMDARs.

In conclusion, we propose that LTP is one of the mechanisms through which cognitive performance is impaired after CHI, and that activation of NMDAR at the subacute phase may rescue their function. The extended loss of NMDAR function provides a therapeu- tic window of at least 24 h for the treatment of cognitive and neurological deficits after head injury and may offer benefit to brain-injured patients.

The authors would like to thank Mrs. Olga Touloumi for her technical assistance. This work was supported by the National Institute of Health grant R01 NS 050285-01 A2 (A.B.)


  • 1.

    Waxweiler, R. J., Thurman, D., Sniezek, J., Sosin, D., and O’Neil,

    • J.

      (1995) Monitoring the impact of traumatic brain injury: a review and update. J. Neurotrauma 12, 509–516

  • 2.

    Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N. H.

      • (1984)

        Elevation of the extracellular concentrations of gluta-

mate and aspartate in rat hippocampus during transient cere- bral ischemia monitored by intracerebral microdialysis. J. Neu- rochem. 43, 1369–1374

  • 3.

    Bullock, R., Zauner, A., Woodward, J., and Young, H. F. (1995) Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke 26, 2187–2189

  • 4.

    Bullock, R., Zauner, A., Myseros, J. S., Marmarou, A., Wood- ward, J. J., and Young, H. F. (1995) Evidence for prolonged release of excitatory amino acids in severe human head trauma. Relationship to clinical events. Ann. N. Y. Acad. Sci. 765, 290– 297; discussion 298

  • 5.

    Davalos, A., Castillo, J., Serena, J., and Noya, M. (1997) Duration of glutamate release after acute ischemic stroke. Stroke 28, 708 –710

  • 6.

    Globus, M. Y., Busto, R., Dietrich, W. D., Martinez, E., Valdes, I., and Ginsberg, M. D. (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobu- tyric acid studied by intracerebral microdialysis. J. Neurochem. 51, 1455–1464

  • 7.

    Nilsson, P., Hillered, L., Ponten, U., and Ungerstedt, U. (1990) Changes in cortical extracellular levels of energy-related metab- olites and amino acids following concussive brain injury in rats.

    • J.

      Cereb. Blood Flow Metab. 10, 631–637

  • 8.

    Wallace, M. C., Teasdale, G. M., and McCulloch, J. (1992) Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat. J. Neurosurg. 76, 127–133

  • 9.

    Owens, J., Tebbutt, A. A., McGregor, A. L., Kodama, K., Magar,

    • S.

      S., Perlman, M. E., Robins, D. J., Durant, G. J., and McCul- loch, J. (2000) Synthesis and binding characteristics of N-(1-




















naphthyl)-N-(3-[(125)I]-iodophenyl)-N-methylguanidine ([(125)I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation. Nucl. Med. Biol. 27, 557–564 Di, X., and Bullock, R. (1996) Effect of the novel high-affinity glycine-site N-methyl-D-aspartate antagonist ACEA-1021 on 125I-MK-801 binding after subdural hematoma in the rat: an in vivo autoradiographic study. J. Neurosurg. 85, 655–661 Kroppenstedt, S. N., Schneider, G. H., Thomale, U. W., and Unterberg, A. W. (1998) Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat. J. Neurotrauma 15, 191–197 Chen, M., Bullock, R., Graham, D. I., Frey, P., Lowe, D., and McCulloch, J. (1991) Evaluation of a competitive NMDA antag- onist (D-CPPene) in feline focal cerebral ischemia. Ann. Neurol. 30, 62–70 Bliss, T. V., and Collingridge, G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 Malenka, R. C., and Nicoll, R. A. (1999) Long-term potentia- tion—a decade of progress? Science 285, 1870–1874 Sanders, M. J., Sick, T. J., Perez-Pinzon, M. A., Dietrich, W. D., and Green, E. J. (2000) Chronic failure in the maintenance of long-term potentiation following fluid percussion injury in the rat. Brain Res. 861, 69–76 Sick, T. J., Perez-Pinzon, M. A., and Feng, Z. Z. (1998) Impaired expression of long-term potentiation in hippocampal slices 4 and 48 h following mild fluid-percussion brain injury in vivo. Brain Res. 785, 287–292 D’Ambrosio, R., Maris, D. O., Grady, M. S., Winn, H. R., and Janigro, D. (1998) Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury. Brain Res. 786, 64–79 Schwarzbach, E., Bonislawski, D. P., Xiong, G., and Cohen, A. S. (2006) Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury. Hippocampus 16, 541–550 Albensi, B. C., Alasti, N., and Mueller, A. L. (2000) Long-term potentiation in the presence of NMDA receptor antagonist arylalkylamine spider toxins. J. Neurosci. Res. 62, 177–185 Biegon, A., Fry, P. A., Paden, C. M., Alexandrovich, A., Tsenter, J., and Shohami, E. (2004) Dynamic changes in N-methyl-D- aspartate receptors after closed head injury in mice: Implica- tions for treatment of neurological and cognitive deficits. Proc. Natl. Acad. Sci. U. S. A. 101, 5117–5122 Biegon, A., Alvarado, M., Budinger, T. F., Grossman, R., Hens- ley, K., West, M. S., Kotake, Y., Ono, M., and Floyd, R. A. (2002) Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain. J. Neurochem. 82, 924–934 Grossman, R., Shohami, E., Alexandrovich, A., Yatsiv, I., Kloog, Y., and Biegon, A. (2003) Increase in peripheral benzodiazepine receptors and loss of glutamate NMDA receptors in a mouse model of closed head injury: a quantitative autoradiographic study. Neuroimage 20, 1971–1981 Miller, L. P., Lyeth, B. G., Jenkins, L. W., Oleniak, L., Panchi- sion, D., Hamm, R. J., Phillips, L. L., Dixon, C. E., Clifton, G. L., and Hayes, R. L. (1990) Excitatory amino acid receptor subtype binding following traumatic brain injury. Brain Res. 526, 103– 107 Sihver, S., Marklund, N., Hillered, L., Langstrom, B., Watanabe, Y., and Bergstrom, M. (2001) Changes in mACh, NMDA and GABA(A) receptor binding after lateral fluid-percussion injury: in vitro autoradiography of rat brain frozen sections. J. Neuro- chem. 78, 417–423 Friedman, W. J. (2001) Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia. Exp. Neurol. 168, 23–31 Temple, M. D., and Hamm, R. J. (1996) Chronic, post-injury administration of D-cycloserine, an NMDA partial agonist, en- hances cognitive performance following experimental brain injury. Brain Res. 741, 246–251 Andersen, J. M., Lindberg, V., and Myhrer, T. (2002) Effects of scopolamine and D-cycloserine on non-spatial reference mem- ory in rats. Behav. Brain Res. 129, 211–216 Lelong, V., Dauphin, F., and Boulouard, M. (2001) RS 67333 and D-cycloserine accelerate learning acquisition in the rat. Neuropharmacology 41, 517–522


Vol. 21

July 2007

The FASEB Journal


Document info
Document views8
Page views8
Page last viewedSat May 21 22:13:07 UTC 2016