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

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.

Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

“…Loss of NMDAR-mediated responses in the ipsilateral hippocampus has been reported previously in several moderate to severe TBI models, 10 including a closed head TBI model showing profound and long-lasting loss of NMDAR function associated with cognitive impairments. [29][30][31] More importantly, this study extends the findings by revealing that NMDARs and LTP in the hippocampus are impaired bilaterally. We observed no difference in AMPARmediated transmission between injury groups.…”

D-Cycloserine 24 and 48 Hours after Asphyxial Cardiac Arrest has No Effect on Hippocampal CA1 Neuropathology

“…Adverse DCS symptoms were not observed nor reported in previous literature. 9 Neurological Deficit Score Assessment Neurological deficit scores were taken at 2 hours after ROSC and daily for 7 days after CA. Total NDS assessed five components: consciousness and respiration, cranial nerve function, motor function, sensory function and coordination.…”

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

“…DCS is known to rescue deficits in GluN-dependent LTP in 23-to 27-month-old wild-type rats (Billard and Rouaud, 2007) and injured mice (Yaka et al, 2007). Two-way ANOVA of LTP levels in untreated and DCS-treated NCAM ϩ/ϩ and NCAM Ϫ/Ϫ mice revealed significant effects of genotype ( p ϭ 0.006) and DCS ( p ϭ 0.003) and a significant interaction between genotype and DCS ( p ϭ 0.002).…”