Phosphoinositide-3-Kinase Activation Controls Synaptogenesis and Spinogenesis in Hippocampal Neurons

The possibility of changing the number of synapses may be an important asset in the treatment of neurological diseases. In this context, the synaptogenic role of the phosphoinositide-3-kinase (PI3K) signaling cascade has been previously demonstrated in Drosophila. This study shows that treatment with a PI3K-activating transduction peptide is able to promote synaptogenesis and spinogenesis in primary cultures of rat hippocampal neurons, as well as in CA1 hippocampal neurons in vivo. In culture, the peptide increases synapse density independently of cell density, culture age, dendritic complexity, or synapse type. The induced synapses also increase neurotransmitter release from cultured neurons. The synaptogenic signaling pathway includes PI3K-Akt. Furthermore, the treatment is effective on adult neurons, where it induces spinogenesis and enhances the cognitive behavior of treated animals in a fear-conditioning assay. These findings demonstrate that functional synaptogenesis can be induced in mature mammalian brains through PI3K activation.

[1]  J. DeFelipe,et al.  Density and morphology of dendritic spines in mouse neocortex , 2006, Neuroscience.

[2]  A. N. van den Pol,et al.  Early synaptogenesis in vitro: Role of axon target distance , 1998, The Journal of comparative neurology.

[3]  D. Abrous,et al.  Upregulation of Polysialylated Neural Cell Adhesion Molecule in the Dorsal Hippocampus after Contextual Fear Conditioning Is Involved in Long-Term Memory Formation , 2007, The Journal of Neuroscience.

[4]  R. Yuste,et al.  Cortical area and species differences in dendritic spine morphology , 2002, Journal of neurocytology.

[5]  Javier DeFelipe,et al.  Spine distribution in cortical pyramidal cells: a common organizational principle across species. , 2002, Progress in brain research.

[6]  M. Sheng,et al.  The growing role of mTOR in neuronal development and plasticity , 2006, Molecular Neurobiology.

[7]  N. Ziv,et al.  Unitary Assembly of Presynaptic Active Zones from Piccolo-Bassoon Transport Vesicles , 2003, Neuron.

[8]  Steven F Dowdy,et al.  Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis , 2004, Nature Medicine.

[9]  E. Gosmanova,et al.  Nerve Growth Factor Signals through TrkA, Phosphatidylinositol 3-Kinase, and Rac1 to Inactivate RhoA during the Initiation of Neuronal Differentiation of PC12 Cells* , 2002, The Journal of Biological Chemistry.

[10]  P. Sanna,et al.  Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Bloom,et al.  Phosphatidylinositol 3-Kinase Is Required for the Expression But Not for the Induction or the Maintenance of Long-Term Potentiation in the Hippocampal CA1 Region , 2002, The Journal of Neuroscience.

[12]  G. Elston,et al.  The occipitoparietal pathway of the macaque monkey: comparison of pyramidal cell morphology in layer III of functionally related cortical visual areas. , 1997, Cerebral cortex.

[13]  C. Hoogenraad,et al.  Control of Dendritic Arborization by the Phosphoinositide-3′-Kinase–Akt–Mammalian Target of Rapamycin Pathway , 2005, The Journal of Neuroscience.

[14]  A. Cáceres,et al.  IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity , 2006, Nature Neuroscience.

[15]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[16]  Yi Rao,et al.  Axon formation: fate versus growth , 2005, Nature Neuroscience.

[17]  K. Kaibuchi,et al.  Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. , 2006, Biochemical and biophysical research communications.

[18]  M. Sheng,et al.  Heterogeneity in the Molecular Composition of Excitatory Postsynaptic Sites during Development of Hippocampal Neurons in Culture , 1998, The Journal of Neuroscience.

[19]  M. Ehlers.  Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system , 2003, Nature Neuroscience.

[20]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[21]  R. Yuste,et al.  Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. , 2000, Cerebral cortex.

[22]  L. Pirola,et al.  Structure and function of phosphoinositide 3-kinases. , 1998, Biochimica et biophysica acta.

[23]  A. Ruiz-Marcos,et al.  The temporal evolution of the distribution of dendritic spines in the visual cortex of normal and dark raised mice , 2004, Experimental Brain Research.

[24]  Shira Knafo,et al.  PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane , 2009, Nature Neuroscience.

[25]  Fabrice P Cordelières,et al.  The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. , 2002, Developmental cell.

[26]  S. Kaech,et al.  Culturing hippocampal neurons , 2006, Nature Protocols.

[27]  Jing Wang,et al.  Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. , 2008, Learning & memory.

[28]  Y. Rao,et al.  Both the Establishment and the Maintenance of Neuronal Polarity Require Active Mechanisms Critical Roles of GSK-3β and Its Upstream Regulators , 2005, Cell.

[29]  Nahum Sonenberg,et al.  The Akt of translational control , 2005, Oncogene.

[30]  Y. Goda,et al.  Actin-Dependent Regulation of Neurotransmitter Release at Central Synapses , 2000, Neuron.

[31]  B. Eickholt,et al.  Phosphoinositide 3-kinase signalling events controlling axonal morphogenesis. , 2007, Biochemical Society transactions.

[32]  P. Seeburg,et al.  Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. , 1995, Science.

[33]  S. R. Datta,et al.  Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway , 2001, Current Opinion in Neurobiology.

[34]  A. Yasui,et al.  BLM is an early responder to DNA double-strand breaks. , 2006, Biochemical and biophysical research communications.

[35]  J. Backer,et al.  Regulation of the p85/p110 Phosphatidylinositol 3′-Kinase: Stabilization and Inhibition of the p110α Catalytic Subunit by the p85 Regulatory Subunit , 1998, Molecular and Cellular Biology.

[36]  Wei Zhang,et al.  Pten Regulates Neuronal Arborization and Social Interaction in Mice , 2006, Neuron.

[37]  R. Ravid,et al.  Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology , 2005, Journal of neurochemistry.

[38]  T. Sudhof,et al.  The synaptic vesicle cycle. , 2004, Annual review of neuroscience.

[39]  G. Waksman,et al.  Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo. , 2001, Cancer research.

[40]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[41]  P. Doherty,et al.  Stimulation of mitogenesis by a cell-permeable PI 3-kinase binding peptide. , 1998, Biochemical and biophysical research communications.

[42]  Noam E Ziv,et al.  Assembly of New Individual Excitatory Synapses Time Course and Temporal Order of Synaptic Molecule Recruitment , 2000, Neuron.

[43]  Yves Grau,et al.  Shaggy, the Homolog of Glycogen Synthase Kinase 3, Controls Neuromuscular Junction Growth in Drosophila , 2004, The Journal of Neuroscience.

[44]  S. Grant,et al.  Phosphatidylinositol 3-Kinase Regulates the Induction of Long-Term Potentiation through Extracellular Signal-Related Kinase-Independent Mechanisms , 2003, The Journal of Neuroscience.

[45]  C. Mello,et al.  Synapsins Are Late Activity-Induced Genes Regulated by Birdsong , 2008, The Journal of Neuroscience.

[46]  A. Gingras,et al.  A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Gean,et al.  A Role for the PI-3 Kinase Signaling Pathway in Fear Conditioning and Synaptic Plasticity in the Amygdala , 2001, Neuron.

[48]  A. Theibert,et al.  Functions of PI 3-kinase in development of the nervous system , 2002, International Journal of Developmental Neuroscience.

[49]  Sholl Da.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953 .

[50]  T. Robbins,et al.  Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues , 1991, Neuroscience.

[51]  N. Ziv,et al.  Cellular and molecular mechanisms of presynaptic assembly , 2004, Nature Reviews Neuroscience.

[52]  E. Hanse,et al.  Glutamate synapse in developing brain: an integrative perspective beyond the silent state , 2009, Trends in Neurosciences.

[53]  M. Kneussel,et al.  Receptors, gephyrin and gephyrin‐associated proteins: novel insights into the assembly of inhibitory postsynaptic membrane specializations , 2000, The Journal of physiology.

[54]  A. Kral,et al.  Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors , 2022 .

[55]  M. Waterfield,et al.  Synthesis and function of 3-phosphorylated inositol lipids. , 2001, Annual review of biochemistry.

[56]  G. D. de Polavieja,et al.  Age-Independent Synaptogenesis by Phosphoinositide 3 Kinase , 2006, The Journal of Neuroscience.

[57]  Ravi Iyengar,et al.  Local Protein Synthesis Mediates a Rapid Increase in Dendritic Elongation Factor 1A after Induction of Late Long-Term Potentiation , 2005, The Journal of Neuroscience.

[58]  R. Lotan,et al.  Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. , 2003, Journal of the National Cancer Institute.

[59]  Y. Jan,et al.  Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines , 1996, Nature.

[60]  C. Stevens,et al.  NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus , 1989, Nature.

[61]  M. Segal.  Dendritic spines and long-term plasticity , 2005, Nature Reviews Neuroscience.

[62]  M. Fischer,et al.  Rapid Actin-Based Plasticity in Dendritic Spines , 1998, Neuron.

[63]  Y. Jan,et al.  Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity , 2003, Cell.

[64]  G. Banker,et al.  Characterization of GABAergic neurons in hippocampal cell cultures , 1994, Journal of neurocytology.

[65]  P. De Camilli,et al.  Synaptogenesis in hippocampal cultures: evidence indicating that axons and dendrites become competent to form synapses at different stages of neuronal development , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[66]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[67]  Rafael Yuste,et al.  Genesis of dendritic spines: insights from ultrastructural and imaging studies , 2004, Nature Reviews Neuroscience.

[68]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[69]  Michael J. Sailor,et al.  Remodeling of Synaptic Actin Induced by Photoconductive Stimulation , 2001, Cell.

[70]  Noam E Ziv,et al.  Principles of glutamatergic synapse formation: seeing the forest for the trees , 2001, Current Opinion in Neurobiology.

[71]  Joseph E LeDoux,et al.  Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. , 1992, Behavioral neuroscience.