At a PI3K crossroads: lessons from flies and rodents

Acebes, Ángel; Morales, Miguel

doi:10.1515/rns.2011.057

Cited by 23 publications

(17 citation statements)

References 61 publications

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“…8B, C; Table 1). Growth effects of PI3K have been demonstrated in interneurons previously and it was proposed that tyrosine kinases other than the dInR could be upstream regulators [45], [63], [70]. Hence, we show that the cell size of DIMM negative neurons can be increased, but not via the dInR.…”

Section: Resultssupporting

confidence: 63%

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Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila

2013

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Neurons and other cells display a large variation in size in an organism. Thus, a fundamental question is how growth of individual cells and their organelles is regulated. Is size scaling of individual neurons regulated post-mitotically, independent of growth of the entire CNS? Although the role of insulin/IGF-signaling (IIS) in growth of tissues and whole organisms is well established, it is not known whether it regulates the size of individual neurons. We therefore studied the role of IIS in the size scaling of neurons in the Drosophila CNS. By targeted genetic manipulations of insulin receptor (dInR) expression in a variety of neuron types we demonstrate that the cell size is affected only in neuroendocrine cells specified by the bHLH transcription factor DIMMED (DIMM). Several populations of DIMM-positive neurons tested displayed enlarged cell bodies after overexpression of the dInR, as well as PI3 kinase and Akt1 (protein kinase B), whereas DIMM-negative neurons did not respond to dInR manipulations. Knockdown of these components produce the opposite phenotype. Increased growth can also be induced by targeted overexpression of nutrient-dependent TOR (target of rapamycin) signaling components, such as Rheb (small GTPase), TOR and S6K (S6 kinase). After Dimm-knockdown in neuroendocrine cells manipulations of dInR expression have significantly less effects on cell size. We also show that dInR expression in neuroendocrine cells can be altered by up or down-regulation of Dimm. This novel dInR-regulated size scaling is seen during postembryonic development, continues in the aging adult and is diet dependent. The increase in cell size includes cell body, axon terminations, nucleus and Golgi apparatus. We suggest that the dInR-mediated scaling of neuroendocrine cells is part of a plasticity that adapts the secretory capacity to changing physiological conditions and nutrient-dependent organismal growth.

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Section: Resultssupporting

confidence: 63%

“…Since these neurons do not grow in response to dInR expression PI3K could possibly be activated by other upstream elements than the dInR. It has indeed been proposed that PI3K-induced growth of brain interneurons (and synapse formation) could be triggered by tyrosine kinases other than the dInR [45], [63], [70].…”

Section: Discussionmentioning

confidence: 99%

Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila

2013

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“…Our group has previously demonstrated that activation of the PI3K–Akt–GSK3 pathway increases synaptogenesis and spinogenesis and improves learning in mammals and invertebrates (Acebes and Morales, 2012). In this study, we present a quantitative analysis showing that PI3K activation improves a contextual learning process and specifically favors the formation of small, “thin” spines in both rat hippocampus and cell culture.…”

Section: Introductionmentioning

confidence: 99%

Learning improvement after PI3K activation correlates with de novo formation of functional small spines

Enriquez-Barreto

Cuesto

Domínguez-Iturza

et al. 2014

Front. Mol. Neurosci.

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PI3K activation promotes the formation of synaptic contacts and dendritic spines, morphological features of glutamatergic synapses that are commonly known to be related to learning processes. In this report, we show that in vivo administration of a peptide that activates the PI3K signaling pathway increases spine density in the rat hippocampus and enhances the animals’ cognitive abilities, while in vivo electrophysiological recordings show that PI3K activation results in synaptic enhancement of Schaffer and stratum lacunosum moleculare inputs. Morphological characterization of the spines reveals that subjecting the animals to contextual fear-conditioning training per se promotes the formation of large spines, while PI3K activation reverts this effect and favors a general change toward small head areas. Studies using hippocampal neuronal cultures show that the PI3K spinogenic process is NMDA-dependent and activity-independent. In culture, PI3K activation was followed by mRNA upregulation of glutamate receptor subunits and of the immediate-early gene Arc. Time-lapse studies confirmed the ability of PI3K to induce the formation of small spines. Finally, we demonstrate that the spinogenic effect of PI3K can be induced in the presence of neurodegeneration, such as in the Tg2576 Alzheimer’s mouse model. These findings highlight that the PI3K pathway is an important regulator of neuronal connectivity and stress the relationship between spine size and learning processes.

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“…Phosphatidylinositide-3 kinase (PI3K) dependent signaling participates in the regulation of several fundamental neuronal processes, including neuronal growth, survival and differentiation, formation of dendrites as well as synaptic plasticity [1]. …”

Section: Introductionmentioning

confidence: 99%

Akt2 Deficiency is Associated with Anxiety and Depressive Behavior in Mice

Leibrock

Ackermann

Hierlmeier

et al. 2013

Cell Physiol Biochem

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Background: The economic burden associated with major depressive disorder and anxiety disorders render both disorders the most common and debilitating psychiatric illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology, successful treatment and prevention of these highly associated disorders have not been identified. Akt2 is a key protein in the phosphatidylinositide-3 (PI3K) / glycogen synthase 3 kinase (GSK3) signaling pathway, which in turn is involved in brain-derived neurotrophic factor (BDNF) effects on fear memory, mood stabilisation and action of several antidepressant drugs. The present study thus explored the impact of Akt2 on behaviour of mice. Methods: Behavioural studies (Open-Field, Light-Dark box, O-Maze, Forced Swimming Test, Emergence Test, Object Exploration Test, Morris Water Maze, Radial Maze) have been performed with Akt2 knockout mice (akt^-/-) and corresponding wild type mice (akt^+/+). Results: Anxiety and depressive behavior was significantly higher in akt^-/- than in akt^+/+ mice. The akt^-/- mice were cognitively unimpaired but displayed increased anxiety in several behavioral tests (O-Maze test, Light-Dark box, Open Field test). Moreover, akt^-/- mice spent more time floating in the Forced Swimming test, which is a classical feature of experimental depression. Conclusion: Akt2 might be a key factor in the pathophysiology of depression and anxiety.

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At a PI3K crossroads: lessons from flies and rodents

Cited by 23 publications

References 61 publications

Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila

Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila

Learning improvement after PI3K activation correlates with de novo formation of functional small spines

Akt2 Deficiency is Associated with Anxiety and Depressive Behavior in Mice

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