Control of Dendritic Arborization by the Phosphoinositide-3′-Kinase–Akt–Mammalian Target of Rapamycin Pathway

Abstract

The molecular mechanisms that determine the size and complexity of the neuronal dendritic tree are unclear. Here, we show that the phosphoinositide-3Ј kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway promotes the growth and branching of dendrites in cultured hippocampal neurons. Constitutively active mutants of Ras, PI3K, and Akt, or RNA interference (RNAi) knockdown of lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome Ten), induced growth and elaboration of dendrites that was blocked by mTOR inhibitor rapamycin and/or by overexpression of eIF-4E binding protein 1 (4E-BP1), which inhibits translation of 5Ј capped mRNAs. The effect of PI3K on dendrites was lost in more mature neurons (Ͼ14 d in vitro). Dendritic complexity was reduced by inhibition of PI3K and by RNAi knockdown of mTOR or p70 ribosomal S6 kinase (p70S6K, an effector of mTOR). A rapamycin-resistant mutant of mTOR "rescued" the morphogenetic effects of PI3K in the presence of rapamycin. By regulating global and/or local protein translation, and as a convergence point for multiple signaling pathways, mTOR could play a central role in the control of dendrite growth and branching during development and in response to activity.

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

“…The PI3K/AKT signaling pathway plays a central role in regulating cell growth, proliferation, and survival under physiologic and pathologic conditions. 34 In addition, in cultured hippocampal neurons, PI3K/AKT signaling has been shown to be involved in axonal sprouting, [22][23][24][25] which is an important mechanism underlying poststroke functional recovery. 17,18,35 Further, recent work has also shown that modulation of GSK-3 after stroke can enhance axonal outgrowth.…”

“…Activation and phosphorylation of PI3K/AKT signaling promotes neurite initiation, outgrowth, and growth cone stability, [22][23][24] as well as contributing to growth and branching of dendrites. 25 In addition, exercise has been shown to facilitate improvements in cognitive function via phosphorylation of AKT and CREB signaling and BNDF expression. [26][27][28] Based on these data, we hypothesized that blocking the combined BDNF and CX1837-induced phosphorylation of AKT using the pan-AKT inhibitor, GSK-690693, would impair the recovery trajectory.…”

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

“…Rapamycin has been previously used to define the mTORC1 contribution to neuronal polarization in neurons cultured longer than 3 days (Jaworski et al. 2005; Choi et al. 2008; Li et al.…”

“…To analyze the role of the mTORC1‐S6K pathway (Laplante and Sabatini 2009) in neuritic initiation we used the mTORC1 inhibitor rapamycin, which has been used in previous studies mostly to define the contribution of mTORC1 to neuronal polarization in neurons cultured for more than 3 days (Jaworski et al. 2005; Choi et al. 2008; Li et al.…”

“…Some elements in this pathway, such as Par3/Par6/aPKC, GSK3 (glycogen synthase kinase 3) or the multiprotein complex mammalian target of rapamycin complex 1 (mTORC1) are implicated directly in the generation and/or maintenance of neuronal polarity and complexity (Jaworski et al. 2005; Jiang et al. 2005; Gartner et al.…”