Taurine-Induced Long-Lasting Enhancement of Synaptic Transmission in Mice: Role of Transporters

Taurine, a major osmolyte in the brain evokes a long-lasting enhancement (LLETAU) of synaptic transmission in hippocampal and cortico-striatal slices. Hippocampal LLETAU was abolished by the GABA uptake blocker nipecotic acid (NPA) but not by the taurine-uptake inhibitor guanidinoethyl sulphonate (GES). Striatal LLETAU was sensitive to GES but not to NPA. Semiquantitative PCR analysis and immunohistochemistry revealed that taurine transporter expression is significantly higher in the striatum than in the hippocampus. Taurine transporter-deficient mice displayed very low taurine levels in both structures and a low ability to develop LLETAU in the striatum, but not in the hippocampus. The different mechanisms of taurine-induced synaptic plasticity may reflect the different vulnerabilities of these brain regions under pathological conditions that are accompanied by osmotic changes such as hepatic encephalopathy

Brain BDNF levels are dependent on cerebrovascular endothelium-derived nitric oxide

International audienceScientific evidence continues to demonstrate a link between endothelial function and cognition. Besides, several studies have identified a complex interplay between nitric oxide (NO) and brain-derived neurotrophic factor (BDNF), a neurotrophin largely involved in cognition. Therefore, this study investigated the link between cerebral endothelium-derived NO and BDNF signaling. For this purpose, levels of BDNF and the phosphorylated form of endothelial NO synthase at serine 1177 (p-eNOS) were simultaneously measured in the cortex and hippocampus of rats subjected to either bilateral common carotid occlusion (n=6), physical exercise (n=6) or a combination of both (n=6) as experimental approaches to modulate flow-induced NO production by the cerebrovasculature. Tropomyosin-related kinase type B (TrkB) receptors and its phosphorylated form at tyrosine 816 (p-TrkB) were also measured. Moreover, we investigated BDNF synthesis in brain slices exposed to the NO donor glyceryl trinitrate. Our results showed increased p-eNOS and BDNF levels after exercise and decreased levels after vascular occlusion as compared to corresponding controls, with a positive correlation between changes in p-eNOS and BDNF (r=0.679). Exercise after vascular occlusion did not change levels of these proteins. Gyceryl trinitrate increased proBDNF and BDNF levels in brain slices, thus suggesting a possible causal relationship between NO and BDNF. Moreover, vascular occlusion, like exercise, resulted in increased TrkB and p-TrkB levels, whereas no change was observed with the combination of both. These results suggest that brain BDNF signaling may be dependent on cerebral endothelium-derived NO production

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive, is due to inherited loss-of-function mutations in the gene encoding a copper-transporting ATPase (Atp7a) on the X chromosome. Although affected patients exhibit signs and symptoms of copper deficiency, the mechanisms resulting in neurologic disease remain unknown. We recently discovered that Atp7a is required for the production of an NMDA receptor-dependent releasable copper pool within hippocampal neurons, a finding that suggests a role for copper in activity-dependent modulation of synaptic activity. In support of this hypothesis, we now demonstrate that copper chelation exacerbates NMDA-mediated excitotoxic cell death in primary hippocampal neurons, whereas the addition of copper is specifically protective and results in a significant decrease in cytoplasmic Ca(2+) levels after NMDA receptor activation. Consistent with the known neuroprotective effect of NMDA receptor nitrosylation, we show here that this protective effect of copper depends on endogenous nitric oxide production in hippocampal neurons, demonstrating in vivo links among neuroprotection, copper metabolism, and nitrosylation. Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo(br) mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury. Taken together, these data reveal a unique connection between copper homeostasis and NMDA receptor activity that is of broad relevance to the processes of synaptic plasticity and excitotoxic cell death