Mammalian target of rapamycin (mTOR) is a key regulator of translational capacity. The mTOR inhibitor rapamycin can prevent forms of protein synthesis-dependent synaptic plasticity such as long-term facilitation in Aplysia and late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of rodents. In the latter model, two issues remain to be addressed: defining the L-LTP phase sensitive to rapamycin and identifying the site of rapamycinsensitive protein synthesis. Here, we show that L-LTP is sensitive to application of rapamycin only during the induction paradigm, whereas rapamycin application after the establishment of L-LTP was ineffective. Second, we observed that Thr-389-phosphorylated p70 S6 kinase (p70 S6K ), the main active phosphoform of the mTOR effector p70 S6K , was induced in an N-methyl-D-aspartateand phosphatidylinositol 3-kinase-dependent manner throughout the dendrites but not in the cell bodies of CA1 neurons in hippocampal slices after L-LTP induction. A similar dendrite-wide activation of p70 S6K was induced in primary hippocampal neurons by depolarization with KCL or glutamate. In primary hippocampal neurons, the sites of dendritic activation of p70 S6K appeared as discrete compartments along dendritic shafts like the hotspots for fast dendritic translation. Conversely, only a subset of dendritic spines also displayed activated p70 S6K . Taken together, the present data suggest that the N-methyl-D-aspartate-, phosphatidylinositol 3-kinase-dependent dendritic activation of the mTOR-p70 S6K pathway is necessary for the induction phase of protein synthesisdependent synaptic plasticity. Newly synthesized proteins in dendritic shafts could be targeted selectively to activity-tagged synapses. Thus, coordinated activation of dendrite-wide translation and synaptic-specific activation is likely to be necessary for long-term synaptic plasticity. F orms of long-term synaptic plasticity that require protein synthesis are believed to be cellular counterparts of longterm memory storage, whereas forms of synaptic plasticity that do not require protein synthesis are believed to be counterparts of short-term memory (1). In particular, dendritic protein synthesis is believed to play a crucial role in long-term synaptic plasticity and memory (1-4). Mammalian target of rapamycin (mTOR) regulates the translation initiation complex in a rapamycin-sensitive manner. It does so primarily through its downstream targets, the kinase p70 S6 kinase (p70 S6K ) and the elongation factor binding protein 4E-BP1. p70 S6K is a major regulator of translation under the control of multiple signal transduction pathways including phosphatidylinositol 3-kinase (PI3K) (5). It increases translational capacity by promoting the expression of several members of the translational machinery whose mRNAs display oligopyrimidine tracts at their 5Ј ends (6). 4E-BP1 is an inhibitor of the cap binding protein eukaryotic initiation factor 4E. 4E-BP1 phosphorylation by mTOR leads to increased translation of capped mRNAs (7). The major d...

Several signal transduction pathways have been implicated in the induction of long-term potentiation (LTP), yet the signal transduction mechanisms behind the maintenance-expression phase of LTP are still poorly understood. We investigated the role of phosphatidylinositol 3-kinase (PI3-kinase) in LTP at Schaffer collateral/commissural fiber-CA1 synapses in rat hippocampal slices using biochemical approaches and extracellular electrophysiological recordings. We observed that PI3-kinase activity was induced in the CA1 region during LTP of field EPSPs (fEPSPs) and that two structurally unrelated PI3-kinase inhibitors, LY294002 and wortmannin, abated established LTP, suggesting that PI3-kinase is involved in the maintenance-expression phase of LTP. However, LTP recovered after washout of the reversible PI3-kinase inhibitor LY294002, confirming that LTP maintenance and expression are distinct events and indicating that PI3-kinase activity is required for LTP expression rather than for its maintenance. Interestingly, preincubation with LY294002 did not prevent LTP induction. In fact, if LY294002 was withdrawn 5 min after high-frequency stimulation, an LTP of fEPSP was seen. Last, a voltage-dependent calcium channel-dependent form of LTP in the CA1 could also be reversibly abated by LY294002, raising the possibility that PI3-kinase could be required for the expression of multiple forms of synaptic potentiation.

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RE, Saban R. VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. Am J Physiol

Background: Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for bladder superficial carcinoma and it is being tested in interstitial cystitis patients, but its precise mechanism of action remains poorly understood. It is not clear whether BCG induces the release of a unique set of cytokines apart from its pro-inflammatory effects. Therefore, we quantified bladder inflammatory responses and alterations in urinary cytokine protein induced by intravesical BCG and compared the results to non-specific pro-inflammatory stimuli (LPS and TNF-α). We went further to determine whether BCG treatment alters cytokine gene expression in the urinary bladder.