Annual Report of Activities CNC 2011 - Center for Neuroscience and ...

292-­‐303 [2011]). This is likely to affect glutamatergic transmission and cell death under excitotoxic conditions, especially in the neonatal period when the transporter is expressed at higher levels. The TrkB.FL receptors for the neurotrophin BDNF are also down-­regulated under excitotoxic conditions and in transient focal ischemia, and this is accompanied by an upregulation of a truncated form of the receptor (TrkB.T) lacking tyrosine kinase activity. Downregulation of TrkB.FL was mediated by calpains whereas the increase in TrkB.T protein levels required transcription and translation activities. Down-­‐regulation of TrkB.FL receptors under excitotoxic conditions was correlated with a decrease in BDNF-­‐induced activation of the Ras/ERK and PLCγ pathways. However, calpain inhibition, which prevents TrkB.FL degradation, did not preclude the decrease in signaling activity of these receptors. On the other hand, incubation with anisomycin, to prevent the upregulation of TrkB.T, protected to a large extent the TrkB.FL signaling activity, suggesting that truncated receptors may act as dominant negatives to downregulate the signaling activity of the full-­‐length receptors. The upregulation of TrkB.T under excitotoxic conditions was correlated with an increase in BDNF-­induced inhibiton of RhoA, a mediator of excitotoxic neuronal death. These results indicate that BDNF protects hippocampal neurons by two distinct mechanisms: through the neurotrophic effects of TrkB.FL receptors and by activation of TrkB.T receptors coupled to inhibition of the excitotoxic signaling. 21