D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury

Rami Yaka*, Anat Biegon, Nikolaos Grigoriadis, Constantina Simeonidou, Savvas Grigoriadis, Alexander G. Alexandrovich, Henri Matzner, Johanna Schumann, Victoria Trembovler, Jeanna Tsenter, Esther Shohami

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Traumatic brain injury triggers a massive glutamate efflux, activation of NMDA receptor channels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurological severity score and object recognition tests, respectively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term potentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic glutamate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI-induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury.

Original languageAmerican English
Pages (from-to)2033-2041
Number of pages9
JournalFASEB Journal
Volume21
Issue number9
DOIs
StatePublished - Jul 2007

Keywords

  • BDNF
  • NMDA receptors
  • Synaptic plasticity
  • Traumatic brain injury

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