Stress Hormones Trk Neurons Into Survival

RESEA r CH HIGHLIGHTS M olec U lar ne U roscience Similar to the in vivo experi- ments, Dex treatment of cultured neurons did not increase levels of Stress hormones Trk BDNF, NGF or NT3, suggesting that the neuroprotective effect of Dex is independent of neurotrophin release. neurons into survival Administration of an inhibitor of the PI3K–AKT pathway abolished Dex- which adult neurogenesis occurs. mediated neuroprotection, whereas Surprisingly, Dex administration did adding a Trk inhibitor only reduced not alter levels of the neurotrophins it; thus, glucocorticoids might also nerve growth factor (NGF), brain- stimulate the PI3K–AKT pathway derived neurotrophic factor (BDNF) through a route that does not involve and neurotrophin 3 (NT3) in the hip- TrkB phosphorylation. pocampus or in the parietal cortex, The mechanism by which gluco- indicating that the phosphorylation corticoids activate Trks is unknown of TrkB by glucocorticoids did not but probably involves the gluco- require increased neurotrophin corticoid receptor, as addition of a production. glucocorticoid receptor antagonist Phosphorylated Trks are activated abolished Dex-mediated neuropro- tyrosine kinases, which can phospho- tection. The glucocorticoid effects rylate other proteins. Thus, adding were slow and lasted for several Glucocorticoids have a bad reputa- Dex or BDNF (the main ligand for hours, which is suggestive of genomic tion. However, although these stress the TrkB receptor) to cortical slices actions. Indeed, Trk activation by hormones can be neurotoxic in activated TrkB and phosphorylated Dex could be abolished by actinomy- high levels, they are also required the intracellular signalling molecules cin D and cycloheximine, inhibitors for neuronal survival, and they AKT, phospholipase Cγ (PLCγ) and of transcription and translation, promote neuronal growth and dif- extracellular signal-regulated kinase respectively. ferentiation and support synaptic (ERK), indicating downstream This study raises some interesting plasticity in the hippocampus. Chao activation of the phosphatidylinositol questions. For example, which genes and colleagues now show that, in 3-kinase (PI3K) pathway. are upregulated by glucocorticoids, rats, the neuroprotective effects of Because neurotrophins promote with Trk phosphorylation as a result? glucocorticoids are mediated by the neuronal survival by binding to Trk And do glucocorticoids also have activation of neurotrophin receptors. receptors, the authors investigated neuroprotective effects in vivo? The authors showed that elevated whether glucocorticoid-induced If they do, it will be interesting to levels of the endogenous glucocorti- activation of TrkB is also neuro- investigate why glucocorticoids coid corticosterone or administration protective. They removed trophic are associated with neurotoxicity of the synthetic glucocorticoid factors from the culture medium of in models of neuron death such as dexamethasone (Dex) resulted in primary hippocampal and cortical experimental hypoxia/ischaemia. phosphorylation of the neurotrophin neurons, a manipulation that nor- Leonie Welberg receptor TrkB in hippocampal cell mally induces apoptosis. However, lysates. In brain sections of Dex- treatment with Dex or BDNF ORIGINAL RESEARCH PAPER Jeanneteau, F., treated rats, phosphorylated TrkB rescued over 30% of neurons. Dex Garabedian, M. J. & Chao, M. V. Activation of Trk was detected in the subgranular and BDNF probably acted through neurotrophin receptors by glucocorticoids provides a neuroprotective effect. zone of the dentate gyrus and in the the same mechanism, as their effects Proc. Natl Acad. Sci. USA 105, 4862–4867 (2008) subventricular zone, two regions in were not additive. natUre reVieWs | NEUROSCIENCE VOlUMe 9 | MaY 2008 © 2008 Nature Publishing Group .

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