Wnt-5a/JNK Signaling Promotes the Clustering of PSD-95 in Hippocampal Neurons

Abstract

During the formation of synapses, specific regions of pre- and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre- and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and non-canonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95. During the formation of synapses, specific regions of pre- and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre- and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and non-canonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95. During the formation of synapses, pre- and postsynaptic sides contain specific molecules that are involved in the regulation and plasticity of synaptic transmission (1.Li Z. Sheng M. Nat. Rev. Mol. Cell Biol. 2003; 4: 833-841Crossref PubMed Scopus (141) Google Scholar, 2.Waites C.L. Craig A.M. Garner C.C. Annu. Rev. Neurosci. 2005; 28: 251-274Crossref PubMed Scopus (375) Google Scholar, 3.Kennedy M.B. Beale H.C. Carlisle H.J. Washburn L.R. Nat. Rev. Neurosci. 2005; 6: 423-434Crossref PubMed Scopus (216) Google Scholar). Although much is known about the molecular mechanisms of synaptic differentiation, major gaps remain in our understanding of the process, particularly with regard to the signals mediating the structuring of the postsynaptic apparatus of central mammalian synapses (2.Waites C.L. Craig A.M. Garner C.C. Annu. Rev. Neurosci. 2005; 28: 251-274Crossref PubMed Scopus (375) Google Scholar, 4.Fox M.A. Umemori H. J. Neurochem. 2006; 97: 1215-1231Crossref PubMed Scopus (93) Google Scholar). At excitatory synapses, the postsynaptic side is characterized by an electrodense thick matrix, called postsynaptic density (PSD). 3The abbreviations used are:PSDpostsynaptic densityDIVday(s) in vitroHEK-293human embryonic kidney 293JNKc-Jun NH2-terminal kinaseACSFartificial cerebrospinal fluidfEPSPfield excitatory postsynaptic potentialPPFpaired pulse facilitationBSD-Xbisindolylmaleimide-XGAPDHglyceraldehyde-3-phosphate dehydrogenaseGFPgreen fluorescent proteinHAhemagglutinin. The PSD contains key molecules involved in the regulation of glutamate receptor targeting and trafficking (1.Li Z. Sheng M. Nat. Rev. Mol. Cell Biol. 2003; 4: 833-841Crossref PubMed Scopus (141) Google Scholar, 5.Petralia R.S. Sans N. Wang Y.X. Wenthold R.J. Mol. Cell Neurosci. 2005; 29: 436-452Crossref PubMed Scopus (188) Google Scholar). There is considerable interest in elucidating the molecular mechanism that controls synaptic targeting and trafficking of these proteins in the postsynaptic region because of their essential role in synaptic plasticity (6.Kennedy M.J. Ehlers M.D. Annu. Rev. Neurosci. 2006; 29: 325-362Crossref PubMed Scopus (277) Google Scholar). Moreover, in neurodegenerative pathologies, such as Alzheimer disease, it has been evidenced that the postsynaptic region, including several proteins of the PSD, is the primary target of the synaptotoxic effect of the amyloid β-peptide (7.Lacor P.N. Buniel M.C. Chang L. Fernandez S.J. Gong Y. Viola K.L. Lambert M.P. 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Wnt proteins through different The of Wnt proteins to in the of the scaffold protein In the canonical pathway, Wnt proteins through to cytoplasmic and the it of Wnt target Annu. Rev. Cell Biol. 2004; 20: PubMed Scopus Google Scholar, M. N. PubMed Scopus Google Scholar). Wnt signaling been that through several through different molecular including of the protein kinase and changes in M. Annu. Rev. Neurosci. 2006; 29: PubMed Scopus Google Scholar). In the we different Wnt ligands are to modulate the and of the postsynaptic regions in mature hippocampal neurons. We that regulates postsynaptic structure and protein directing the clustering of PSD-95 density through the Moreover, we that Wnt-5a modulates the synaptic that the pathway controls synaptic structure and function of the excitatory postsynaptic of mammalian from and from bisindolylmaleimide-X and from mouse mouse mouse mouse and from mouse from the of of and from Cell and with from and with from fluorescent protein from the different a of several that this work a from Salinas a of of and receptor a of of Wnt embryonic kidney 293 cells in with and cells by with and of and Wnt-5a and M. Toledo E.M. R.J. Inestrosa N.C. J. Neurosci. 2007; PubMed Scopus Google Scholar) cells Wnt-5a ligands cells in with and for The of Wnt ligands in the by using an the Wnt ligand we the different Wnt ligands with for of the neurons. primary hippocampal from rat M. Toledo E.M. R.J. Inestrosa N.C. J. Neurosci. 2007; PubMed Scopus Google Scholar) and in with for The with with and with for on to the of in the of with without for and TAT-TI-JIP with Wnt-5a for with with and with the to different on a density of with in for with for with and with PSD-95 to used as a neurite of on with a using a used for with and using of PSD-95 from for of field for in with to neuronal PSD-95 of for and the of diffuse dendritic PSD-95 using regions of interest from dendritic Nat. 2006; PubMed Scopus Google Scholar). In PSD-95 using a of the of diffuse as a PSD-95 and with the using of neurite to of PSD-95 clusters and total dendritic PSD-95 to of dendritic of of with a in and for PSD-95 using the of from for in with Wnt-5a ligand for with for for total protein in a and with and in for and for for and the to in a and the M. Toledo E.M. R.J. Inestrosa N.C. J. Neurosci. 2007; PubMed Scopus Google Scholar). The to the cytoplasmic and the using the proteins to and using of using and as of and receptor and as of slices to from slices from the artificial cerebrospinal fluid using a and in for In to in to slices to an with and by with a The the field potential I. M.J. Inestrosa N.C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) with to an with and that in the of the of The on from the presynaptic by field excitatory postsynaptic by by a to an The in the of the The paired pulse facilitation by and are the of the and postsynaptic using of that an are as of and as the of the from the of as in the by using with Wnt including and are in the of adult and in hippocampal using a mammalian Wnt for I. M.J. Inestrosa N.C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). we that short term to Wnt-7a Wnt-5a ligand modulates the synaptic and synaptic transmission in hippocampal I. M.J. Inestrosa N.C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we Wnt ligands can regulate the postsynaptic region in mature hippocampal neurons. to Wnt-7a ligand for changes in the clustering of the postsynaptic protein PSD-95, with to the in the clustering of the presynaptic protein as I. M.J. Inestrosa N.C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). hippocampal with the Wnt-5a an in the PSD-95 density and and without affecting the clustering of the presynaptic protein the postsynaptic protein PSD-95 without affecting the presynaptic protein in a new the of the Wnt-5a ligand Wnt-5a ligands with a receptor protein to the Wnt their with A. J. S. A. PubMed Scopus Google Scholar). The of the of the of PSD-95 clusters by Wnt-5a and Moreover, to that the effect in PSD-95 clustering is to Wnt-5a and to the of proteins in the we used a ligand from the of the Wnt-5a ligand that the Wnt-5a in A. J. T. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus (93) Google Scholar). We found a in the of PSD-95 clusters hippocampal to ligand for of in the ligand the clustering of the presynaptic protein The short term effect of the Wnt-5a ligand in the clustering of PSD-95 a in PSD-95 clusters of of Wnt-5a the in the PSD-95 density is to an in the expression of total PSD-95 protein, we the of PSD-95 protein in a total of hippocampal neurons. Wnt-5a the total of PSD-95 in the in we the in the of PSD-95 clusters The of PSD-95 clusters in excitatory is with the of mature dendritic (6.Kennedy M.J. Ehlers M.D. Annu. Rev. Neurosci. 2006; 29: 325-362Crossref PubMed Scopus (277) Google Scholar, Annu. Rev. Neurosci. 2007; 30: PubMed Scopus Google Scholar). that Wnt-5a induces clustering of PSD-95 in dendritic with the to the PSD-95 in spines. in for the of PSD-95 and to Wnt-5a for an in the of indicate that Wnt-5a Wnt-7a the postsynaptic region of mammalian synapse by the clustering of PSD-95. an in the clustering of PSD-95 the total of this protein we Wnt-5a the of PSD-95 clusters to a of PSD-95. changes in the PSD-95 the new clusters of PSD-95 Wnt-5a ligand are to the of PSD-95 clusters Wnt-5a induces the clustering of PSD-95 through recruitment of PSD-95 from a diffuse pool with and different of PSD-95 clusters The to Wnt-5a the of PSD-95 that Wnt-5a the of PSD-95 clusters that the in the of PSD-95 clusters is to a in the of PSD-95 in in to Wnt-5a induces the of PSD-95 the PSD-95 Moreover, we the PSD-95 Wnt-5a the PSD-95 and the PSD-95 it is that of PSD-95 clusters the of PSD-95 it that new PSD-95 clusters from a diffuse that Wnt-5a the of PSD-95 the of PSD-95 that of PSD-95 clusters that new clusters of PSD-95 from a diffuse dendritic cytoplasmic pool without affecting the of PSD-95 in the that Wnt-5a induces new PSD-95 clusters from of PSD-95 protein a studies that PSD-95 is a protein that in to it to the postsynaptic E. S. N. A. R.A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). a of PSD-95 and cytoplasmic hippocampal with that the of PSD-95 with the induces the of PSD-95 from and to the and and PSD-95 from and to the and as evidenced E. S. N. A. R.A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, T. A. H. S. J. Neurosci. 2006; PubMed Scopus Google Scholar). we Wnt-5a induces a in the of PSD-95. We found that hippocampal with Wnt-5a for of PSD-95 in the with to the and by the of and receptor and the of and a in the PSD-95 in the cytoplasmic and by the of and and the of and receptor are with the that new clusters of PSD-95 from a diffuse dendritic cytoplasmic Wnt ligands act through canonical Wnt pathways, on the Biol. 2006; 4: Scopus Google Scholar). the effect of Wnt-5a Wnt-7a in the clustering of PSD-95 is to the of different Wnt pathways, we mature hippocampal with the Wnt-5a and Wnt-7a ligands and the of the Wnt we that Wnt-7a induces the of in a the of I. M.J. Inestrosa N.C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Toledo E.M. R.J. Inestrosa N.C. J. Neurosci. 2007; PubMed Scopus Google Scholar). to Wnt-5a in the of of Moreover, Wnt-5a and Wnt-7a ligands in their to the canonical Wnt pathway, Wnt-7a Wnt-5a and The of the Wnt-7a ligand with the in the of Wnt-5a Wnt-7a induces the clustering of PSD-95, these that Wnt-5a ligand the of the canonical Wnt pathway to the clustering of PSD-95. Wnt ligands can act through the non-canonical Wnt pathways, such as and (12.Ciani L. Salinas P.C. Nat. Rev. Neurosci. 2005; 6: 351-362Crossref PubMed Scopus (521) Google Scholar, M. Annu. Rev. Neurosci. 2006; 29: PubMed Scopus Google Scholar). Wnt-5a non-canonical Wnt in hippocampal we a on the pathway and a on the pathway M. Annu. Rev. 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Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar) In hippocampal the of by Wnt-5a and the the clustering of PSD-95 by Wnt-5a without affecting the clustering of PSD-95 the dendritic formation with Wnt-5a induces the clustering of postsynaptic proteins pathways, we used for the known of these and to the of and protein kinase of the pathway and to the of of the pathway with Wnt-5a ligand for in the of the pathway the PSD-95 clustering by Wnt-5a and with Wnt-5a in the of the clustering of PSD-95 by Wnt-5a and that the pathway is in the clustering of PSD-95, we used a S.B. D. A. Salinas P.C. Nat. Neurosci. 2005; PubMed Scopus Google Scholar, M.J. J. Y. 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We found that of dendritic contain PSD-95 clusters and that Wnt-5a induces the of total and PSD-95 by is that the in the of clusters of PSD-95 in it is necessary to the of the to for the PSD-95 is as a the we found that Wnt-5a can the of PSD-95 clusters without the total expression of PSD-95 and that Wnt-5a the density of PSD-95 clusters to a of PSD-95. for formation of PSD-95 been has been that of PSD-95 clusters can in S. M.A. A. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). the PSD-95 clusters can by recruitment from a diffuse pool of PSD-95 the synapse with of T. Y. Garner C.C. Mol. Cell Neurosci. PubMed Scopus Google Scholar). Our of PSD-95 clusters suggests that of PSD-95 the in PSD-95 clustering by because the of PSD-95 and the of the PSD-95 are with the that new PSD-95 clusters by Wnt-5a from a diffuse pool of PSD-95. our In fact, we an in the PSD-95 pool and a in the diffuse PSD-95 pool The to PSD-95 with of been as of the R.S. S. F. A. Wenthold R.J. M. J. Neurosci. PubMed Google Scholar). proteins are by the Wnt-5a that are by studies are to this In this we that a specific A. S. Y. A.M. S. A. PubMed Scopus Google Scholar), and a peptide that the of affecting the 2006; PubMed Scopus Google Scholar), the in the clustering of PSD-95 by that a signaling pathway is by Wnt-5a to the clustering of PSD-95 in hippocampal neurons. Moreover, we demonstrated that the of hippocampal with a and a can the effect of Wnt-5a on PSD-95 of as used by Rosso S.B. D. A. Salinas P.C. Nat. Neurosci. 2005; PubMed Scopus Google Scholar) and M.J. J. Y. Sheng M. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) TAT-TI-JIP the clustering of PSD-95 with an that the postsynaptic structure in hippocampal neurons. The in the clustering of PSD-95 by the Wnt-5a ligand is with the in mature dendritic with PSD-95 in their that the non-canonical signaling in the of the postsynaptic suggests that PSD-95 is to PSD-95 from a diffuse pool to the synaptic E. S. N. A. R.A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). suggests that of of PSD-95 is necessary to PSD-95 to the postsynaptic M.J. J. Y. Sheng M. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). We demonstrated that Wnt-5a the of is because the of in PSD-95 by has been to regulate the synaptic of PSD-95 M.J. J. Y. Sheng M. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Moreover, Rosso S.B. D. A. Salinas P.C. Nat. Neurosci. 2005; PubMed Scopus Google Scholar) that dendritic development in hippocampal by a signaling that involved in the regulation of the neuronal We the of the regulation of to the of Wnt-5a on the PSD-95 The mechanism used by the Wnt-5a/JNK pathway to form clusters of PSD-95 it is that of these the of PSD-95 from a diffuse pool in the to a PSD-95 regulates receptor and dendritic changes that synaptic has been demonstrated that of PSD-95 to functional synapses and the and of V. R.A. J. Neurosci. 2003; PubMed Google Scholar). 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