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

Rami Yaka^*,1, Anat Biegon, Nikolaos Grigoriadis, Constantina Simeonidou, Savvas Grigoriadis^||, Alexander G. Alexandrovich^*, Henri Matzner^*, Johanna Schumann^*, Victoria Trembovler^*, Jeanna Tsenter^*,¶ and Esther Shohami^*

^* Department of Pharmacology, School of Pharmacy, Hebrew University, Jerusalem, Israel;

Brookhaven National Laboratory, Upton, New York, USA;

Department of Neurology, AHEPA University Hospital, Greece;

Department of Physiology, Faculty of Medicine, Aristotle University of Thessaloniki, Greece;

^|| Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel; and

^¶ Department of Rehabilitation, Hadassah Medical Center, Jerusalem, Israel

¹Correspondence: Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail: yaka{at}md.huji.ac.il

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.—Yaka, R., Biegon, A., Grigoriadis, N., Simeonidou, C., Grigoriadis, S., Alexandrovich, A. G., Matzner, H., Schumann, J., Trembovler, V., Tsenter, J., Shohami, E. D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.

Key Words: traumatic brain injury • NMDA receptors • synaptic plasticity • BDNF

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