Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway

Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1. Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1. Insulin and its receptor are widely dispersed throughout the brain with the highest density located in the olfactory bulb, cerebral cortex, hypothalamus, and hippocampus, where they are thought to subserve a number of functions including regulation of glucose metabolism, food intake and body weight, fertility and reproduction, learning, memory, and attention (1Hill J.M. Lesniak M.A. Pert C.B. Roth J. Neuroscience. 1986; 17: 1127-1138Crossref PubMed Scopus (323) Google Scholar, 2Wozniak M. Rydzewski B. Baker S.P. Raizada M.K. Neurochem. Int. 1993; 22: 1-10Crossref PubMed Scopus (194) Google Scholar, 3Wickelgren I. Science. 1998; 280: 517-519Crossref PubMed Scopus (151) Google Scholar, 4Stockhorst U. de Fries D. Steingrueber H.J. Scherbaum W.A. Physiol. Behav. 2004; 83: 47-54Crossref PubMed Scopus (157) Google Scholar). Brain insulin receptors are present in particularly high concentrations in neurons, and in much lower levels in glia (5Schwartz M.W. Figlewicz D.P. Baskin D.G. Woods S.C. Porte Jr., D. Endocr. Rev. 1992; 13: 387-414PubMed Google Scholar). Although the mRNA of insulin receptors is largely localized in neuronal somata, abundant insulin receptors are found in both cell bodies and synapses (5Schwartz M.W. Figlewicz D.P. Baskin D.G. Woods S.C. Porte Jr., D. Endocr. Rev. 1992; 13: 387-414PubMed Google Scholar, 6Marks J.L. Maddison J. Eastman C.J. J. Neurochem. 1998; 50: 774-781Crossref Scopus (22) Google Scholar, 7Abbott M.A. Wells D.G. Fallon J.R. J. Neurosci. 1999; 19: 7300-7308Crossref PubMed Google Scholar). However, very little is known about the functional significance of synaptic insulin receptors in the neurons. Recently, several studies have drawn links between insulin signaling and intracellular trafficking and plasma membrane expression of ion channels and neurotransmitter receptors at the central nervous system synapses. For example, it has been shown that insulin rapidly recruits functional GABAA receptors to postsynaptic domains in hippocampal neurons, resulting in a long-lasting enhancement of GABAA receptor-mediated synaptic transmission (8Wan Q. Xiong Z.G. Man H.Y. Ackerley C.A. Braunton J. Lu W.Y. Becker L.E. MacDonald J.F. Wang Y.T. Nature. 1997; 388: 686-690Crossref PubMed Scopus (454) Google Scholar). In addition, we and other investigators have provided evidence that insulin can promote the internalization of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors from the synaptic membrane of neurons, which causes a long-term depression of excitatory synaptic transmission in the hippocampus and cerebellum (9Man H.Y. Lin J.W. Ju W.H. Ahmadian G. Liu L. Becker L.E. Sheng M. Wang Y.T. Neuron. 2000; 25: 649-662Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar, 10Wang Y.T. Linden D.J. Neuron. 2000; 25: 635-647Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 11Huang C.C. You J.L. Lee C.C. Hsu K.S. Mol. Cell. Neurosci. 2003; 24: 831-841Crossref PubMed Scopus (33) Google Scholar, 12Huang C.C. Lee C.C. Hsu K.S. J. Neurochem. 2004; 89: 217-231Crossref PubMed Scopus (93) Google Scholar). Moreover, insulin enhances N-methyl-d-aspartate (NMDA) 1The abbreviations used are: NMDA, N-methyl-d-aspartate; PSD, postsynaptic density; PSD-95, protein postsynaptic density-95; aCSF, artificial cerebrospinal fluid; 4E-BP1, 4E-binding protein 1; eIF4E, eukaryotic initiator 4E; eIF4G, eukaryotic initiator 4G; p70S6K, p70S6 kinase; IGF-1, insulin-like growth factor-1; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; LY303511, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one; AG1024, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile; RT, reverse transcriptase. 1The abbreviations used are: NMDA, N-methyl-d-aspartate; PSD, postsynaptic density; PSD-95, protein postsynaptic density-95; aCSF, artificial cerebrospinal fluid; 4E-BP1, 4E-binding protein 1; eIF4E, eukaryotic initiator 4E; eIF4G, eukaryotic initiator 4G; p70S6K, p70S6 kinase; IGF-1, insulin-like growth factor-1; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; LY303511, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one; AG1024, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile; RT, reverse transcriptase. receptor-mediated synaptic transmission at the hippocampal CA1 synapses (13Liu L. Brown 3rd, J.C. Webster W.W. Morrisett R.A. Monaghan D.T. Neurosci. Lett. 1995; 192: 5-8Crossref PubMed Scopus (103) Google Scholar) and potentiates the activity of recombinant NMDA receptors expressed in Xenopus oocytes (14Liao G.Y. Leonard J.P. J. Neurochem. 1999; 73: 1510-1519Crossref PubMed Scopus (42) Google Scholar). Although these findings highlight the role of insulin signaling in modulating synaptic functions, it is not yet clear how exactly insulin contributes to these diverse actions at the molecular levels. The postsynaptic density (PSD) is a specialization of cytoskeleton at the synaptic junction and serves as an important organizer of the postsynaptic signal transduction machinery (15Ziff E.B. Neuron. 1997; 19: 1163-1174Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). The PSD forms a disc that consists of cytoskeletal and regulatory proteins, some of which contact the cytoplasmic domains of ion channels or neurotransmitter receptors in the postsynaptic membrane (16Ehlers M.D. Mammen A.L. Lau L.F. Huganir R.L. Curr. Opin. Cell Biol. 1996; 8: 484-489Crossref PubMed Scopus (90) Google Scholar). One of fundamental structural proteins within the PSD is PSD-95, a 95-kDa scaffolding protein containing multiple PSD-95/Discs large/zona occluens-1 domains to anchor and associate glutamate receptors with other functional proteins in the PSD (17Hering H. Sheng M. Nat. Rev. Neurosci. 2001; 2: 880-888Crossref PubMed Scopus (691) Google Scholar, 18Kim E. Sheng M. Nat. Rev. Neurosci. 2004; 5: 771-781Crossref PubMed Scopus (1194) Google Scholar). Although the function of the PSD-95 protein at the synapses is not yet clear, evidence from the PSD-95 mutant or expression studies has demonstrated that PSD-95 may play a modulatory role in control of the synaptic transmission (19El-Husseini A.E. Schnell E. Chetkovich D.M. Nicoll R.A. Bredt D.S. Science. 2000; 290: 1364-1368Crossref PubMed Google Scholar), bidirectional synaptic plasticity (20Migaud M. Charlesworth P. Dempster M. Webster L.C. Watabe A.M. Makhinson M. He Y. Ramsay M.F. Morris R.G. Morrison J.H. O'Dell T.J. Grant S.G. Nature. 1998; 396: 433-439Crossref PubMed Scopus (948) Google Scholar, 21Ehrlich I. Malinow R. J. Neurosci. 2004; 24: 916-927Crossref PubMed Scopus (413) Google Scholar), maturation of excitatory synapses (19El-Husseini A.E. Schnell E. Chetkovich D.M. Nicoll R.A. Bredt D.S. Science. 2000; 290: 1364-1368Crossref PubMed Google Scholar, 22Stein V. House D.R. Bredt D.S. Nicoll R.A. J. Neurosci. 2003; PubMed Google Scholar), and M. J.M. Grant S.G. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). A that from these is and how PSD-95 protein can at synaptic to the synaptic A has demonstrated that rapidly dendritic PSD-95 protein synthesis in J. Neurosci. 2003; PubMed Google Scholar). that insulin receptor and its are of PSD fractions and are at the synapses in the hippocampal neurons, it is of to the between insulin receptor activation and PSD-95 protein the evidence that brief insulin treatment the synthesis of PSD-95 protein in local dendritic the activation of PI3K-Akt-mTOR signaling pathway. This may a important to synaptic transmission and plasticity in hippocampal area CA1. were to the by the and of slices were from to by the C.C. Hsu K.S. J. Neurosci. 1999; 19: PubMed Google Scholar). In were by and the were in artificial and with a in slices were in a of with and at for at 1 The of the was and glucose at and with were to of for the and of fractions were as D.G. M.F. Fallon J.R. J. Neurosci. 2001; PubMed Google Scholar). the CA1 were in and with and at for 1 were by a The was at for and was with at a protein of from at slices were The CA1 were in containing a of protein and 1 1 1 1 and to and of proteins, and with a were and at at for The was for protein the was in the were in containing and for 1 and for at with that PSD-95 Cell Cell Cell Cell or Cell was with for 1 and the The phosphorylation were and with the or that were from Cell were by of PSD-95 mRNA in of PSD-95 mRNA between and we used was isolated from the hippocampal CA1 or to the We used of in reverse a synthesis was as were for and were for of at for at for and at for of hippocampal CA1 and were to a and with The density from the was by from the hippocampal CA1 to a the in the for mRNA The used in are: PSD-95, and and and and was the the 1 in of of the and of was the for for for and for 1 The signal was by the to the in of the target were detected as in between were by to the concentrations in the of were and with AG1024, LY294002, LY303511, wortmannin, actinomycin D, and rapamycin were in and at the of the The of in the was which the insulin signaling or PSD-95 not Insulin and were from LY294002, wortmannin, and actinomycin were from and AG1024, LY303511, and for insulin-like growth receptor were from of the are The significance of the between the was by of were to of Insulin the PSD-95 in of was to the activation of insulin receptors regulates the PSD-95 protein of hippocampal slices with insulin for resulted in in levels of PSD-95 protein as of from area CA1 a of the of PSD-95 protein was increased by of control after of insulin increase PSD-95 protein we treatment to the of in In a PSD-95 protein levels for at after of insulin In addition, the of insulin PSD-95 protein expression to the levels of protein were not after insulin treatment receptors are very similar to insulin receptors and insulin to both insulin and the is with about S.P. Rev. Physiol. PubMed Google Scholar, Y. 1993; PubMed Scopus Google Scholar). were to the in PSD-95 protein by insulin were by the activation of hippocampal slices were with a the receptor which has been shown to and its activity Y.T. Linden D.J. Neuron. 2000; 25: 635-647Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 12Huang C.C. Lee C.C. Hsu K.S. J. Neurochem. 2004; 89: 217-231Crossref PubMed Scopus (93) Google Scholar, Jr., P. J. Biol. 1993; Full Text PDF Google Scholar). This treatment the insulin-induced in PSD-95 protein expression The of of receptor the of insulin is not of the of treatment to the treatment the in PSD-95 protein expression induced by insulin receptor we used AG1024, a tyrosine kinase that some the insulin receptors M. E. D. 1997; PubMed Scopus Google Scholar), to or not the of insulin PSD-95 protein expression was the insulin shown in AG1024 prevented the insulin-induced in PSD-95 protein indicate that activation of insulin receptor signaling serves to the expression of PSD-95 protein in the hippocampal area CA1. in PSD-95 PI3K-Akt-mTOR activation of insulin receptors by insulin a of signal transduction the signaling pathway that contributes to the insulin-induced in the PSD-95 protein the for activation was of the hippocampal slices with the inhibitor, LY294002 C.J. Brown J. Biol. Full Text PDF PubMed Google Scholar), insulin-induced in the PSD-95 protein expression were also with the of inhibitor, not In the inactive analogue of LY294002, LY303511 did not affect the of insulin of LY294002, wortmannin, or LY303511 the levels of PSD-95 that the activation of is for the insulin-induced in PSD-95 protein expression in hippocampal area CA1. the PSD-95 protein expression by insulin was of an increase in the new protein we the hippocampal slices with the protein synthesis inhibitor, anisomycin insulin shown in anisomycin the insulin-induced in PSD-95 protein the of mRNA synthesis to we the of the inhibitor, actinomycin the of In to the translation inhibitor, actinomycin for the in PSD-95 protein by insulin We also insulin the levels of PSD-95 mRNA by but we a with the that the in PSD-95 protein induced by insulin were from an activation of mRNA and that mRNA was present at the of the The signaling pathway has been shown to play a role in several of the translational machinery in mammalian Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), and insulin can pathway to the activity of several translation regulatory 2004; PubMed Scopus Google Scholar). We the in PSD-95 protein expression by insulin a the inhibitor, rapamycin, was shown in of the hippocampal slices with rapamycin for insulin-induced in PSD-95 protein to the levels of PSD-95 We that insulin the new PSD-95 protein synthesis in a and manner. the for the activation of the PI3K-Akt-mTOR signaling pathway in insulin-induced in PSD-95 protein we used to the levels of forms of Akt, and after hippocampal slices were with For we used an for which is the activation of and is essential for kinase activity D.R. J. 1999; PubMed Scopus Google Scholar). For Akt, we used an for which is for activation of D.R. M. B. P. P. J. 1996; PubMed Scopus Google Scholar). For mTOR, we used an for which has been shown to important in the control of activity P. Jr., J.C. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Roth R.A. Jr., J.C. U. 1998; PubMed Scopus Google Scholar). stimulation of the hippocampal slices with insulin for a increase in the phosphorylation of Akt, and as of from the CA1 area In addition, the insulin-induced increase in the phosphorylation of Akt, and was to control levels within after of is that Akt, and are of we LY294002 the insulin-induced in the phosphorylation of Akt, and We found that LY294002 but not LY303511 the in Akt, and phosphorylation induced by insulin LY294002 LY303511 the levels of Akt, and tyrosine kinase AG1024 also the insulin-induced in the phosphorylation of Akt, and these indicate that of Akt, and to the insulin receptor signaling in hippocampal area CA1. Insulin the of and activation of can contribute to translational by phosphorylation of 4E-binding protein 1 (4E-BP1) that to and the function of the translation eIF4E, we regulatory protein may have a role in insulin-induced in PSD-95 protein We used an for a whose phosphorylation is for the of and its from the B. S.P. M. R. 2001; PubMed Scopus Google Scholar). of the hippocampal slices with insulin for increased phosphorylation of Furthermore, the insulin-induced in the phosphorylation of were by AG1024, LY294002, and rapamycin LY303511 to the in phosphorylation induced by insulin not activation may also translation by or phosphorylation of other protein as B. S.P. M. R. 2001; PubMed Scopus Google Scholar). We the in PSD-95 protein expression by insulin are the phosphorylation of after insulin treatment was We used an for and whose phosphorylation are for activation G. Cell 1999; PubMed Scopus Google Scholar). the hippocampal slices were with insulin for the phosphorylation of was increased Furthermore, the insulin-induced in the phosphorylation of were by AG1024, LY294002, and rapamycin LY303511 to the in phosphorylation induced by the that activation of both and is for the insulin-induced increase in PSD-95 protein expression in hippocampal area CA1. of PSD-95 is evidence that mRNA can in the dendrites of hippocampal CA1 Y. G. J. Neurosci. 1999; 19: PubMed Google Scholar), the of protein synthesis is the cell the and the synthesis of PSD-95 protein from the synaptic we a that for synaptic fractions E.B. J.L. J.W. J. Neurosci. 5: PubMed Google Scholar). the of PSD-95 we the mRNA by from both the and fractions and its with that of other The were by and detected by it is not a However, did that the mRNA PSD-95 is present in hippocampal CA1 and that its is similar to known protein kinase In mRNA was not detected in the that the used in are the synaptic the expression of PSD-95 mRNA within synaptic we an in the fractions to PSD-95 mRNA located to the synaptic the translational control as we detected in shown in an increase in the PSD-95 protein expression was after insulin treatment for with with hippocampal AG1024 and LY294002 LY303511 has insulin-induced in PSD-95 protein In addition, of the with protein synthesis inhibitors, anisomycin and rapamycin, but not the inhibitor, actinomycin D, also prevented the in PSD-95 by insulin these findings suggest that the insulin stimulation of PSD-95 new protein synthesis in The present a new synaptic mechanism that to the modulation of local PSD-95 protein expression in hippocampal area CA1. findings suggest a role for insulin in the activation of dendritic translation machinery a PI3K-Akt-mTOR signaling pathway. Insulin and its translation regulatory and p70S6K, to the translation of the dendritic scaffolding protein We also demonstrate that insulin the translation of PSD-95 in a manner. Although a of has the of PSD-95 protein in neuronal (19El-Husseini A.E. Schnell E. Chetkovich D.M. Nicoll R.A. Bredt D.S. Science. 2000; 290: 1364-1368Crossref PubMed Google Scholar, M. Charlesworth P. Dempster M. Webster L.C. Watabe A.M. Makhinson M. He Y. Ramsay M.F. Morris R.G. Morrison J.H. O'Dell T.J. Grant S.G. Nature. 1998; 396: 433-439Crossref PubMed Scopus (948) Google Scholar, 21Ehrlich I. Malinow R. J. Neurosci. 2004; 24: 916-927Crossref PubMed Scopus (413) Google Scholar, 22Stein V. House D.R. Bredt D.S. Nicoll R.A. J. Neurosci. 2003; PubMed Google Scholar, M. J.M. Grant S.G. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), the or that the PSD-95 protein expression have not yet been A has shown that can a increase in PSD-95 new protein synthesis in a J. Neurosci. 2003; PubMed Google Scholar). Although is the to the the levels of PSD-95 the did not the of PSD-95 protein The present that insulin of PSD-95 protein expression in slices and fractions in hippocampal area both of which are inhibited by translation inhibitor, suggesting that a new PSD-95 protein synthesis is in the In to the translation inhibitor, actinomycin D, a of did not affect the insulin-induced in the PSD-95 protein synthesis is not mRNA but the of PSD-95 mRNA with we that mRNA PSD-95 protein is located to synaptic fractions in a similar to that of known dendritic protein kinase Although we have been to the that local protein synthesis in other the of translation may dendrites of CA1 neurons. This is by the that the levels of insulin-induced in PSD-95 protein are not between the slices and has been shown to an important of insulin signaling in the brain M. Rydzewski B. Baker S.P. Raizada M.K. Neurochem. Int. 1993; 22: 1-10Crossref PubMed Scopus (194) Google Scholar, J. M. Neuroscience. PubMed Scopus Google Scholar, R. D. L. Brain 1996; PubMed Scopus Google Scholar). the functional significance of insulin and its receptors at the synapses have been in the of regulation of intracellular trafficking and plasma membrane expression of ion channels and neurotransmitter receptors (9Man H.Y. Lin J.W. Ju W.H. Ahmadian G. Liu L. Becker L.E. Sheng M. Wang Y.T. Neuron. 2000; 25: 649-662Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar, 10Wang Y.T. Linden D.J. Neuron. 2000; 25: 635-647Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 11Huang C.C. You J.L. Lee C.C. Hsu K.S. Mol. Cell. Neurosci. 2003; 24: 831-841Crossref PubMed Scopus (33) Google Scholar, 12Huang C.C. Lee C.C. Hsu K.S. J. Neurochem. 2004; 89: 217-231Crossref PubMed Scopus (93) Google Scholar, L. Brown 3rd, J.C. Webster W.W. Morrisett R.A. Monaghan D.T. Neurosci. Lett. 1995; 192: 5-8Crossref PubMed Scopus (103) Google Scholar, G.Y. Leonard J.P. J. Neurochem. 1999; 73: 1510-1519Crossref PubMed Scopus (42) Google Scholar). evidence that the diverse insulin actions may the expression of insulin receptor tyrosine kinase and signal transduction M.A. Wells D.G. Fallon J.R. J. Neurosci. 1999; 19: 7300-7308Crossref PubMed Google Scholar). Although the of the insulin receptor for insulin-induced in PSD-95 protein synthesis are suggest that the proteins a signaling PI3K, Akt, and The that insulin-induced the in PSD-95 protein synthesis is by inhibitors, LY294002 and wortmannin, and inhibitor, rapamycin, a pathway and This is with an that activation of the PI3K-Akt-mTOR pathway by can a increase in PSD-95 protein expression in J. Neurosci. 2003; PubMed Google Scholar). new PSD-95 protein are that in translational the activation of may contribute to translation by that The is by eIF4G, a scaffolding translation that several of the translation the mRNA its with 2004; PubMed Scopus Google Scholar, Jr., J.C. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S.G. M.A. 1998; PubMed Scopus Google Scholar). the activation of may also translation or phosphorylation and activation of other protein as 2004; PubMed Scopus Google Scholar, S.G. M.A. 1998; PubMed Scopus Google Scholar). The activation of protein which can in translation of that of translation machinery 2004; PubMed Scopus Google Scholar). This is by the that insulin treatment to increased phosphorylation of and p70S6K, both of which with increased levels of PSD-95 protein translation and are inhibited by rapamycin activation of by insulin may both translation and of protein at synapses. In addition, the of these molecular of translation machinery in the dendritic was demonstrated by and in the synaptic fractions Brain 2003; PubMed Scopus Google Scholar) or hippocampal in G. H. U. PubMed Scopus Google Scholar). Although it is thought that rapamycin is a highly of mTOR, the that rapamycin other or Although show that insulin can new PSD-95 protein synthesis in hippocampal area it is the insulin has been that can insulin and to evidence insulin it has been demonstrated that the of insulin from the hippocampal was at about D.G. Woods S.C. M. D.M. Porte Jr., D. PubMed Scopus Google Scholar). the insulin concentrations at the synaptic may not are it is to the of insulin used in the present is or the that mRNA is in synaptic it is known that dendrites can mRNA E. Nat. Rev. Neurosci. 2004; 5: PubMed Scopus Google Scholar) and new protein synthesis can induced in isolated dendrites and after of neuronal to G. Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) or activity M.A. Science. 2004; PubMed Scopus Google Scholar, J. G. T.J. C.C. Nat. Neurosci. 2004; PubMed Scopus Google Scholar), little is known about may exactly in demonstrate for the that mRNA PSD-95 is present at the synapses and can stimulated activation of insulin receptors in brain In addition, may at in the that insulin NMDA receptor-mediated synaptic at hippocampal CA1 synapses (13Liu L. Brown 3rd, J.C. Webster W.W. Morrisett R.A. Monaghan D.T. Neurosci. Lett. 1995; 192: 5-8Crossref PubMed Scopus (103) Google Scholar) and NMDA receptor expression in Xenopus oocytes (14Liao G.Y. Leonard J.P. J. Neurochem. 1999; 73: 1510-1519Crossref PubMed Scopus (42) Google Scholar). is that PSD-95 protein with the of the domains M. E. Sheng M. J. Neurosci. 1996; PubMed Google Scholar) may and NMDA receptor In the suggest that the dendritic scaffolding protein PSD-95 may a of insulin signaling at the synapses of hippocampal area CA1. of synaptic modulation induced by insulin by local translation of PSD-95 mRNA in neuronal the significance of insulin induced the in the dendritic PSD-95 protein synthesis in remains to that the PSD-95 protein is as an to ion channels and neurotransmitter receptors or a signaling at the postsynaptic membrane E. Sheng M. Nat. Rev. Neurosci. 2004; 5: 771-781Crossref PubMed Scopus (1194) Google Scholar), and that evidence a role for proteins in of and of receptor proteins J. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. J. Neurosci. 2001; PubMed Google Scholar, H. 2001; PubMed Scopus Google Scholar), may an important role in synaptic and